EP2548865A1 - Novel bis-indolic derivatives, their uses in particular as antibacterials - Google Patents
Novel bis-indolic derivatives, their uses in particular as antibacterials Download PDFInfo
- Publication number
- EP2548865A1 EP2548865A1 EP11305964A EP11305964A EP2548865A1 EP 2548865 A1 EP2548865 A1 EP 2548865A1 EP 11305964 A EP11305964 A EP 11305964A EP 11305964 A EP11305964 A EP 11305964A EP 2548865 A1 EP2548865 A1 EP 2548865A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- mmol
- aryl
- indol
- defined above
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000844 anti-bacterial effect Effects 0.000 title claims description 35
- 229940088710 antibiotic agent Drugs 0.000 title claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 195
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 36
- 229910003827 NRaRb Inorganic materials 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 239000003242 anti bacterial agent Substances 0.000 claims description 32
- 230000003115 biocidal effect Effects 0.000 claims description 28
- 241000894006 Bacteria Species 0.000 claims description 21
- 229910052740 iodine Inorganic materials 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 241000191967 Staphylococcus aureus Species 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229940124307 fluoroquinolone Drugs 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 229960003405 ciprofloxacin Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 241000191940 Staphylococcus Species 0.000 claims description 8
- 108010015899 Glycopeptides Proteins 0.000 claims description 7
- 102000002068 Glycopeptides Human genes 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229960003085 meticillin Drugs 0.000 claims description 6
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 150000003952 β-lactams Chemical class 0.000 claims description 5
- 229910017711 NHRa Inorganic materials 0.000 claims description 4
- 108010059993 Vancomycin Proteins 0.000 claims description 4
- 229960003165 vancomycin Drugs 0.000 claims description 4
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 4
- 229910003204 NH2 Inorganic materials 0.000 claims description 3
- 230000000843 anti-fungal effect Effects 0.000 claims description 3
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 2
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 229960002549 enoxacin Drugs 0.000 claims description 2
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229960003376 levofloxacin Drugs 0.000 claims description 2
- 229960003702 moxifloxacin Drugs 0.000 claims description 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 2
- 229960001180 norfloxacin Drugs 0.000 claims description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 2
- 229960001699 ofloxacin Drugs 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 229960004236 pefloxacin Drugs 0.000 claims description 2
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 206010041925 Staphylococcal infections Diseases 0.000 claims 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 claims 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 38
- 238000002360 preparation method Methods 0.000 abstract description 4
- 229940124350 antibacterial drug Drugs 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 128
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 126
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 86
- 238000005160 1H NMR spectroscopy Methods 0.000 description 65
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 64
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 58
- 239000000203 mixture Substances 0.000 description 57
- 150000001412 amines Chemical class 0.000 description 47
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 43
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- 239000011734 sodium Substances 0.000 description 40
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 34
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 27
- 229910001868 water Inorganic materials 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 25
- 230000001580 bacterial effect Effects 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- ZNBGBHISQKMEPA-UHFFFAOYSA-N 2-oxoacetyl chloride Chemical compound ClC(=O)C=O ZNBGBHISQKMEPA-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 239000006260 foam Substances 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 15
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 14
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- JFCOEINQFUJWPU-UHFFFAOYSA-N tert-butyl n-[2-amino-2-(5-bromo-1h-indol-3-yl)ethyl]carbamate Chemical compound C1=C(Br)C=C2C(C(N)CNC(=O)OC(C)(C)C)=CNC2=C1 JFCOEINQFUJWPU-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000013058 crude material Substances 0.000 description 9
- 150000003141 primary amines Chemical class 0.000 description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- -1 CO-aryl Chemical group 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 8
- 239000002054 inoculum Substances 0.000 description 8
- 239000001282 iso-butane Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000008261 resistance mechanism Effects 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 8
- FPEGGKCNMYDNMW-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxoacetyl chloride Chemical class C1=CC=C2C(C(=O)C(=O)Cl)=CNC2=C1 FPEGGKCNMYDNMW-UHFFFAOYSA-N 0.000 description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- VEMBYRAOQDXUMU-UHFFFAOYSA-N 1-(5-bromo-1h-indol-3-yl)ethanamine Chemical compound C1=C(Br)C=C2C(C(N)C)=CNC2=C1 VEMBYRAOQDXUMU-UHFFFAOYSA-N 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 239000007832 Na2SO4 Substances 0.000 description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 241000194017 Streptococcus Species 0.000 description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- QVDYYQXUNAQSNI-UHFFFAOYSA-N ethyl acetate;pentane Chemical compound CCCCC.CCOC(C)=O QVDYYQXUNAQSNI-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
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- 241000894007 species Species 0.000 description 6
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- RMCQCVYGHWTDSP-UHFFFAOYSA-N 1-(5-bromo-1h-indol-3-yl)ethanone Chemical compound C1=C(Br)C=C2C(C(=O)C)=CNC2=C1 RMCQCVYGHWTDSP-UHFFFAOYSA-N 0.000 description 5
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- DREIZUYRWZZCQR-JAIQZWGSSA-N n-[1-(5-bromo-1h-indol-3-yl)ethyl]-1-phenylmethanimine oxide Chemical compound C=1NC2=CC=C(Br)C=C2C=1C(C)[N+](\[O-])=C\C1=CC=CC=C1 DREIZUYRWZZCQR-JAIQZWGSSA-N 0.000 description 4
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- 229960004889 salicylic acid Drugs 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LGVDZUYBKYYTIP-UHFFFAOYSA-N tert-butyl 3-(1h-indol-3-yl)-4-[2-(1h-indol-3-yl)-2-oxoacetyl]piperazine-1-carboxylate Chemical compound C1=CC=C2C(C(=O)C(=O)N3CCN(CC3C=3C4=CC=CC=C4NC=3)C(=O)OC(C)(C)C)=CNC2=C1 LGVDZUYBKYYTIP-UHFFFAOYSA-N 0.000 description 1
- DZIHXDMDMNVFNL-UHFFFAOYSA-N tert-butyl 3-(1h-indol-3-yl)piperazine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCNC1C1=CNC2=CC=CC=C12 DZIHXDMDMNVFNL-UHFFFAOYSA-N 0.000 description 1
- LIFMTWLOMCPJTQ-UHFFFAOYSA-N tert-butyl 3-(5-bromo-1h-indol-3-yl)-4-[2-(5-bromo-1h-indol-3-yl)-2-oxoacetyl]piperazine-1-carboxylate Chemical compound C1=C(Br)C=C2C(C(=O)C(=O)N3CCN(CC3C=3C4=CC(Br)=CC=C4NC=3)C(=O)OC(C)(C)C)=CNC2=C1 LIFMTWLOMCPJTQ-UHFFFAOYSA-N 0.000 description 1
- RBPDDDXRYZKEKZ-UHFFFAOYSA-N tert-butyl 3-(5-bromo-1h-indol-3-yl)-4-hydroxypiperazine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN(O)C1C1=CNC2=CC=C(Br)C=C12 RBPDDDXRYZKEKZ-UHFFFAOYSA-N 0.000 description 1
- QZBAZVDJTXDQHS-UHFFFAOYSA-N tert-butyl 3-(5-bromo-1h-indol-3-yl)piperazine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCNC1C1=CNC2=CC=C(Br)C=C12 QZBAZVDJTXDQHS-UHFFFAOYSA-N 0.000 description 1
- OICIFXHIYBPJSC-UHFFFAOYSA-N tert-butyl 4-hydroxy-3-(1h-indol-3-yl)piperazine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN(O)C1C1=CNC2=CC=CC=C12 OICIFXHIYBPJSC-UHFFFAOYSA-N 0.000 description 1
- IIYFMTUDQNNYOW-UHFFFAOYSA-N tert-butyl N-[2-amino-2-(6-fluoro-1H-indol-3-yl)ethyl]carbamate Chemical compound FC1=CC=C2C(C(N)CNC(=O)OC(C)(C)C)=CNC2=C1 IIYFMTUDQNNYOW-UHFFFAOYSA-N 0.000 description 1
- VWIHRVGOMHXARA-UHFFFAOYSA-N tert-butyl N-[2-amino-2-(6-iodo-1H-indol-3-yl)ethyl]carbamate Chemical compound IC1=CC=C2C(C(N)CNC(=O)OC(C)(C)C)=CNC2=C1 VWIHRVGOMHXARA-UHFFFAOYSA-N 0.000 description 1
- IASJPJJIRUPGQA-UHFFFAOYSA-N tert-butyl n-[2-(1h-indol-3-yl)-2-[[2-(1h-indol-3-yl)-2-oxoacetyl]amino]ethyl]carbamate Chemical compound C1=CC=C2C(C(NC(=O)C(=O)C=3C4=CC=CC=C4NC=3)CNC(=O)OC(C)(C)C)=CNC2=C1 IASJPJJIRUPGQA-UHFFFAOYSA-N 0.000 description 1
- SEBRDBPXJSHXMN-UHFFFAOYSA-N tert-butyl n-[2-(5-bromo-1h-indol-3-yl)-2-[(2,2,2-trifluoroacetyl)amino]ethyl]carbamate Chemical compound C1=C(Br)C=C2C(C(NC(=O)C(F)(F)F)CNC(=O)OC(C)(C)C)=CNC2=C1 SEBRDBPXJSHXMN-UHFFFAOYSA-N 0.000 description 1
- OHDNXMPLWZUCLF-UHFFFAOYSA-N tert-butyl n-[2-(5-bromo-1h-indol-3-yl)-2-[[2-(5-bromo-1h-indol-3-yl)-2-oxoacetyl]amino]ethyl]carbamate Chemical compound C1=C(Br)C=C2C(C(NC(=O)C(=O)C=3C4=CC(Br)=CC=C4NC=3)CNC(=O)OC(C)(C)C)=CNC2=C1 OHDNXMPLWZUCLF-UHFFFAOYSA-N 0.000 description 1
- XYYMVTSULJEXOH-UHFFFAOYSA-N tert-butyl n-[2-[benzyl(hydroxy)amino]-2-(6-chloro-1h-indol-3-yl)ethyl]carbamate Chemical compound C=1NC2=CC(Cl)=CC=C2C=1C(CNC(=O)OC(C)(C)C)N(O)CC1=CC=CC=C1 XYYMVTSULJEXOH-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- TVPNFKRGOFJQOO-UHFFFAOYSA-N topsentin b1 Chemical class C1=CC=C2C(C3=CN=C(N3)C(=O)C=3C4=CC=C(C=C4NC=3)O)=CNC2=C1 TVPNFKRGOFJQOO-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 230000000007 visual effect Effects 0.000 description 1
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- 239000000230 xanthan gum Substances 0.000 description 1
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- KGPGQDLTDHGEGT-JCIKCJKQSA-N zeven Chemical compound C=1C([C@@H]2C(=O)N[C@H](C(N[C@H](C3=CC(O)=C4)C(=O)NCCCN(C)C)=O)[C@H](O)C5=CC=C(C(=C5)Cl)OC=5C=C6C=C(C=5O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@H](O5)C(O)=O)NC(=O)CCCCCCCCC(C)C)OC5=CC=C(C=C5)C[C@@H]5C(=O)N[C@H](C(N[C@H]6C(=O)N2)=O)C=2C(Cl)=C(O)C=C(C=2)OC=2C(O)=CC=C(C=2)[C@H](C(N5)=O)NC)=CC=C(O)C=1C3=C4O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O KGPGQDLTDHGEGT-JCIKCJKQSA-N 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to novel bis-indolic derivatives, processes for their preparation, and their potential use as new antibacterial drugs.
- Penicillin G was the first natural antibiotic identified, first by Ernst Duchesne in the 19 th century, then rediscovered in 1928 by Alexander Fleming.
- Resistance mechanisms include the inactivation of the drug by specific enzymes, alteration of the antibiotic target, bacterial wall impermeability to antibiotic entry, and efflux of the antibiotic from the bacterial cytosol. These mechanisms usually develop within a few years after a new drug is introduced into clinical practice.
- Staphylococcus aureus may resist to antibiotics by the production of enzymes (e.g., penicillinase leading to resistance to penicillin G, transferases leading to resistance to aminoglycosides), by the modification of natural targets (e.g., acquisition of mecA gene in methicillin-resistant strains), or by efflux systems (e.g., NorA and fluoroquinolone resistance).
- enzymes e.g., penicillinase leading to resistance to penicillin G, transferases leading to resistance to aminoglycosides
- natural targets e.g., acquisition of mecA gene in methicillin-resistant strains
- efflux systems e.g., NorA and fluoroquinolone resistance
- oxazolidinones and cyclic lipopeptides have been the two only new antibiotic classes with a complete original structure approved in the treatment of Gram-positive bacterial infections.
- Linezolide and daptomycin are the only commercialized compounds of the oxazolidinone and lipopeptide classes, respectively.
- Their antibacterial spectrum comprises most of Gram-positive bacteria responsible for human infections, including multi-drug resistant strains such as the vancomycin-resistant Enterococcus sp. (VRE) and methicillin-resistant Staphylococcus aureus (MRSA).
- VRE vancomycin-resistant Enterococcus sp.
- MRSA methicillin-resistant Staphylococcus aureus
- carbapenems have been developed. They have a broad antibacterial spectrum because of greater stability to the action of most ⁇ -lactamases. Three carbapenems are currently commercialized: imipenem, meropenem and ertapenem. A fourth one, doripenem, is close to the commercialization ( M. Wolff, M.-L. Joly-Guillou, O. Pajot, « Les carbaticiannèmes » Réanimation, 2009, 18, 5199-5208 ). Their antibacterial spectrum encompasses most of aerobic and anaerobic bacteria. However, they are not effective against multi-drug resistant bacteria such as MRSA, methicillin-resistant coagulase-negative staphylococci, penicillin-resistant E. faecium, carbapenemase-producing Enterobacteraceae or Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.
- MRSA methicillin-resistant coagulase-negative staphylococci
- ceftobiprole and ceftaroline Two new cephalosporins (ceftobiprole and ceftaroline) with a broad antibacterial spectrum and an activity against MRSA are currently in phase III clinical trial.
- telavancin is the only compound to be commercialized, the two others being still in phase II clinical trials.
- indole derivatives a new class of molecules showing antimicrobial activity named indole derivatives.
- MIC minimum inhibitory concentrations
- One objective of the present invention is to provide new compounds, with new structures, and an improved antibacterial activity as compared to monoindole derivatives, including against bacteria resistant to multiple antibiotics.
- Another aim of the invention is to provide new compounds with an original structure liable to inhibit the NorA efflux pump of Staphylococcus aureus, responsible for fluoroquinolone resistance in this species.
- Another aim of the invention is to provide new compounds having both an antibiotic activity when used alone or in association with fluoroquinolones, and a NorA efflux pump inhibition activity.
- Still another aim is to provide pharmaceutical compositions comprising said new compounds.
- the present invention relates to compounds of the following formula I: wherein:
- linear alkyl group from C 1 to C 7 is meant a group such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.
- branched alkyl group is meant an alkyl group as defined above bearing substituents selected from the list of linear alkyl groups defined above, said linear alkyl group being also liable to be branched.
- cycloalkyl group from C 3 to C 7 is meant a group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Such groups can also be substituted by a linear or branched alkyl group as defined above.
- cycloalkyl group applies also to the entire specification.
- aryl refers to any functional group or substituent derived from a simple aromatic ring.
- the aryl can be substituted by one or more groups chosen independently among an halogen, a linear or branched (C 1 -C 7 )-alkyl, a (C 3 -C 7 )-cycloalkyl, CN, CF 3 , OH, OR x , NH 2 , NHR x , NR x R y , R x and R y being a linear or branched (C 1 -C 7 )-alkyl, a (C 3 -C 7 )-cycloalkyl, an aryl substituted or not, CH 2 -aryl, CO-(C 1 -C 7 )-alkyl or cycloalkyl, CO-aryl, CO 2 H, CO 2 -(C 1 -C 7 )-alkyl or cycloalkyl,
- heteromatic refers to a compound having the characteristics of an aromatic compound whilst having at least one non-carbon atom in the ring.
- the heteroaromatic can be substituted by one or more groups chosen independently among those defined for aryl.
- a basic group such as the nitrogen of the indole moiety or an amino group present on the molecule can be under a salt form, the salt being any pharmaceutically acceptable salt obtained by reaction of an inorganic acid, an organic acid or a halogenoalkyl, on an amino group to give a quaternary ammonium.
- inorganic acid allowing obtaining pharmaceutically acceptable salts include, without being limited to them, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, formic acid, monohydrogenocarbonic acid, phosphoric acid, monohydrogenophosphoric acid, dihydrogenophosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid.
- the molecule can also bear an acid group, and as at least one substituent of the indole moiety or of the aryl or heteroaromatic groups can be a phenol, they can also be under a pharmaceutically acceptable salt form.
- the salt can be obtained with organic or mineral bases, to give for instance alkali metal salts such as, lithium, sodium, potassium salts.
- compounds of the invention can be the R or the S enantiomer, a racemic mixture of both enantiomers or a mixture comprising 0.01%-99.99% of the R enantiomer and 99.99%-0.01% of the S enantiomer.
- the inventors have found that some compounds bearing two indole moieties, present an antibiotic activity on bacteria, and said compounds presenting an original structure with regards to all existing antibiotics; they are promising candidate not to develop a resistance or to develop only late resistance.
- compounds of the invention present also both intrinsic antibacterial activity and NorA efflux pump inhibitor activity.
- the present invention relates to compounds defined above, wherein:
- R 7 represents H, OH, OR a , R a being as defined above.
- compounds of the invention are compounds wherein R and R 7 are not joined and presenting an antibacterial activity and/or NorA efflux pump inhibitor.
- the present invention relates to compounds defined above, wherein:
- compounds of the invention are cyclic compounds presenting an antibacterial activity and/or NorA efflux pump inhibitor.
- the present invention relates to compounds defined above, wherein the antibacterial activity is against Gram-positive and Gram-negative bacteria.
- Another advantage of the invention is to provide antibiotics active both against Gram-positive and Gram-negative bacteria.
- Gram-positive bacteria refers to the two bacterial phyla defined in the Bergey's manual of systematic bacteriology (2 nd edition, G. M. Garrity (ed.), Springer, 2005 ), Actinobacteria, and Firmicutes, and include the well known genera Staphylococcus, Streptococcus; Enterococcus, Listeria and Bacillus,
- Gram-negative bacteria refers to 22 bacterial phyla defined in the Bergey's manual of systematic bacteriology (2 nd edition, G. M. Garrity, Springer, 2005 ), Aquificae, Thermotogae, Thermodesulfobacteria, Deinococcus-Thermus, Chrysiogenetes, Chloroflexi, Thermomicrobia, Nitrospira, Deferribacteres, Cyanobacteria, Chlorobia, Proteobacteria, Planctomycetes, Chlamydiae, Spirochaetes, Fibrobacteres, Acidobacteres, Bacteroidetes, ,Fusobacteria, Verrucomicrobia, Dictyoglomi, and Gemmatimonadetes.
- Proteobacteria include a large number of human pathogens such as the Enterobacteriaceae, Pseudomonadaceae, Vibrionaceae, Moraxellaceae, Neisseriaceae and Pasteurellaceae families.
- the present invention relates to compounds of formula I defined above, wherein said compounds are narrow spectrum antibiotics having the advantage not to alter the intestinal microbiota.
- narrow-spectrum compounds of the invention are able to act as an antibiotic effective against only specific families of bacteria (in the invention Gram-positive Staphylococcus aureus and coagulase-negative Staphylococcus species, and to a lesser extent Gram-positive Streptococcus and Bacillus species and Gram-negative Haemophilus species).
- the present invention relates to compounds defined above, wherein said bacteria are resistant to conventional antibiotics.
- Compounds of the invention are not only active against sensitive bacteria but also present the advantage to be active against bacteria resistant to currently available antibiotics.
- the present invention relates to compounds defined above, wherein the antibacterial activity is against Staphylococcus species, in particular Staphylococcus aureus, especially Staphylococcus aureus resistant to ⁇ -lactams (including methicillin-resistant strains, also referred as MRSA), Staphylococcus aureus resistant to glycopeptides (vancomycin-resistant or glycopeptides-resistant strains, also referred as VISA or GISA) and Staphylococcus aureus resistant to fluoroquinolones.
- Staphylococcus species in particular Staphylococcus aureus, especially Staphylococcus aureus resistant to ⁇ -lactams (including methicillin-resistant strains, also referred as MRSA), Staphylococcus aureus resistant to glycopeptides (vancomycin-resistant or glycopeptides-resistant strains, also referred as VISA or GISA) and Staphylococcus aureus resistant to fluoroquinolones.
- Compounds of the invention are also active against coagulase-negative Staphylococcus species such as Staphylococcus epidermidis, including strains resistant to ⁇ -lactam or fluoroquinolone antibiotics.
- Compounds of the invention also present the advantage to be active against bacteria that are multi-resistant, i.e., resistant to several classes of antibiotics including those cited above.
- the present invention relates to compounds defined above, having further an antifungal and/or antiviral activity.
- a further advantage of the compounds of the invention is that they present not only an antibacterial activity but also an antifungal activity or an antiviral activity. Some of the compounds also present the triple activity.
- the present invention relates to compounds defined above, of the following formula II: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R' 1 , R' 2 , R' 3 , R' 4 , R' 5 , R' 6 and R are as defined above.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, of the following formula II-1: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R' 1 , R' 2 , R' 3 , R' 4 , R' 5 , R' 6 and R are as defined above.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, of the following formula II-3: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R' 1 , R' 2 , R' 3 , R' 4 , R' 5 , R' 6 and R are as defined above.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II wherein R 6 and R' 6 represent H.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II wherein R 2 , R 5 , R' 2 and R' 5 represent H.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II wherein R 7 represent H.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II, wherein R 6 and R' 6 are different.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II, wherein R 1 is different from R' 1 and/or R 2 is different from R' 2 , and/or R 3 is different from R' 3 and/or R 4 is different from R' 4 and/or R 5 is different from R' 5 .
- R and R 7 are not joined together to form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, having the formula I or II, wherein R 1 is similar to R' 1 , and/or R 2 is similar to R' 2 , and/or R 3 is similar to R' 3 , and/or R 4 is similar to R' 4 , and/or R 5 is similar to R' 5 and/or R 6 is similar to R' 6 .
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, of the following formula III: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R' 1 , R' 2 , R' 3 , R' 4 , R' 5 and R are as defined above.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, of the following formula IV: wherein R 1 , R 3 , R 4 , R 7 , R' 1 , R' 3 , R' 4 and R are as defined above.
- R and R 7 are not joined together and do not form a cycle of formula I-a or I-b.
- the present invention relates to compounds defined above, of the following formula V wherein:
- the present invention relates to compounds of formula V defined above, wherein:
- At least one halogen atom must be present in R 3 , R 4 , R' 3 or R' 4 position, more preferably two halogens atoms (one halogen atom on each indole cycle) must be present and more preferably said halogen is Br.
- the present invention relates to compounds defined above, of the following general formula VI: wherein:
- the present invention relates to compounds of formula VI defined above, wherein the compound of formula VI is selected from the group consisting of :
- the present invention relates to compounds defined above, of the following general formula VII: wherein:
- the present invention relates to compounds of formula VII defined above, having the following structure:
- the present invention relates to compounds defined above, of the following formula V-1 wherein:
- the present invention relates to compounds of formula V-1 defined above, having the following structure:
- One of the advantages of the compounds of the invention having a NorA efflux pump inhibition activity is the possibility of said compounds to reverse the resistance of a bacterial strain that became resistant to a classical antibiotic if they are administered with said classical antibiotic provided that classical antibiotic and compounds of the invention belong to different families of antibiotics.
- the present invention relates to compounds defined above, of the following general formula VIII: wherein:
- the present invention relates to compounds of formula VIII defined above, having the following structures:
- the present invention relates to compounds defined above, of the following general formula VIII-1: wherein:
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I, in association with a pharmaceutically acceptable vehicle.
- pharmaceutically acceptable vehicle denotes in particular cellulose, starch, benzyl alcohol, polyethylene glycol, gelatin, lactose, polysorbate, magnesium or calcium stearate, xanthan gum, guar, alginate, colloidal silica.
- compositions according to the invention can be used by oral, parenteral, topic, or rectal route or in aerosols.
- compositions for oral administration tablets, pills, gelatin capsules, powders or granules can be used.
- the active ingredient according to the invention is mixed with one or more inert diluents or adjuvants, such as saccharose, lactose or starch.
- these compositions can comprise substances other than the diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.
- compositions for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used.
- inert diluents such as water or paraffin oil
- These compositions can also comprise substances other than the diluents, for example wetting products, sweeteners or flavourings.
- compositions for parenteral administration can be sterile solutions or emulsions.
- solvent or vehicle water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate can be used.
- These compositions can also contain adjuvants, in particular wetting agents, isotoning agents, emulsifiers, dispersants and stabilizers.
- the sterilization can be carried out in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the moment of use in sterile water or any other injectable sterile medium.
- compositions for topical administration can be for example creams, ointments, lotions or aerosols.
- compositions for rectal administration are suppositories or rectal capsules, which, in addition to the active ingredient, contain excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
- compositions can also be aerosols.
- the compositions can be stable sterile solutions or solid compositions dissolved at the moment of use in pyrogen-free sterile water, in serum or any other pharmaceutically acceptable vehicle.
- the active ingredient is finely divided and combined with a diluent or hydrosoluble solid vehicle, for example dextran, mannitol or lactose.
- the present invention relates to a pharmaceutical composition defined above, administrable by oral route at a dose comprised from about 10 mg/kg to about 200 mg/kg.
- the present invention relates to a pharmaceutical composition defined above, under a form liable to be administrable by oral route at a dose comprised from 100 mg to 1,500 mg, in particular from 100 mg to 1,000 mg, in particular from 100 to 500 mg.
- Said pharmaceutical composition can be administered 2 or 3 times per day.
- the present invention relates to a pharmaceutical composition defined above, administrable by intraveinous route at a dose comprised from about 5 ⁇ g/kg to about 50 mg/kg.
- the present invention relates to a pharmaceutical composition defined above, under a form liable to be administrable by intraveinous route at a dose comprised from 0,1 mg to 1000 mg, in particular from 10 mg to 1,000 mg, in particular from 10 to 500 mg, in particular from 10 to 100 mg.
- Said pharmaceutical composition can be administered 2 or 3 times per day.
- the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula V.
- the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VI, such as compounds 4 or 5.
- the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VII, such as compound 3 .
- the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula V-1, such as compound 2 .
- the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VIII, such as compounds 6a, 6b, 6c, 6d, 6e, 6f or 7 .
- the present invention relates to a pharmaceutical composition defined above, comprising further:
- Said antibiotic compound must be from a different family of the one of the compounds of the invention.
- a compound of the invention is a NorA efflux pump inhibitor
- administration of said compound with an antibiotic for which the bacterium is resistant allows to restore the antibiotic activity against bacteria that became resistant to said antibiotic.
- the 2-(1 H -indol-3-yl)-2-oxoacetyl chlorides (8a) and (8c) were prepared according the procedure described in the literature. See : X. Guinchard, Y. Vallée, J.-N. Denis, « Total synthesis of marine sponge bis(indole) alkaloids of the topsentin class » J. Org. Chem. 2007, 72, 3972-3975 ; X. Guinchard, Y. Vallée, J.-N. Denis, « Total syntheses of brominated marine sponge alkaloids » Org. Lett. 2007, 9, 3761-3764 .
- the compound (8d) can be obtained from 5-chloroindole (ad) according to the procedure described in this patent.
- the compound (8e) can be obtained from 6-chloroindole (ae) according to the procedure described in this patent.
- the compound (8f) can be obtained from 5-fluoroindole (af) according to the procedure described in this patent.
- the compound (8g) can be obtained from 6-fluoroindole (ag) according to the procedure described in this patent.
- the compounds (8h-i) and (k-I) can be obtained from indoles (ai-i) and (ak-I) according to the procedure described in this patent.
- the compound (8j) can be obtained from 4-bromoindole (aj) according to the procedure described in this patent.
- a cold solution of hydrochloric acid was prepared by reaction of 1.12 mL (1.25 g, 15.91 mmol) of freshly distilled acetyl chloride with 40 mL of dry methanol. This solution was stirred at 0 °C during 15 min and then was added a mixture of both indole ( aa ) (0.93 g, 7.95 mmol) and nitrone ( ea ) (2.1 g, 7.95 mmol) in 20 mL of methanol. The reaction was stirred at 0 °C during 1 hour to completion. A saturated aqueous solution of NaHCO 3 was then added.
- a cold solution of hydrochloric acid was prepared by reaction of 0.143 mL (157 mg, 2.0 mmol) of freshly distilled acetyl chloride with 5 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was added to a mixture of both nitrone (ea) (1.0 mmol) and indole (aa-I) (1.0 mmol) in 5 mL of dry methanol. The reaction mixture was stirred at 0 °C during 2 hours to completion. A saturated aqueous solution of NaHCO 3 was then added.
- the compound (Xg) (340 mg, 0.85 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 6-fluoroindole (ag) (135 mg, 1.0 mmol) as a white solid. Yield: 85%.
- the compound (Xi) can be obtained from nitrone (ea) and 6-iodoindole (ai) according to the procedure described in this patent.
- the compound (Xk) can be obtained from nitrone (ea) and 7-bromoindole (ak) according to the procedure described in this patent.
- the compound (XI) can be obtained from nitrone (ea) and 2-bromoindole (al) according to the procedure described in this patent.
- the compound (Yi) can be obtained from indolic N -hydroxylamine (Xi) according to the procedure described in this patent.
- the compounds (Yj) , (Yk) and (Yl) can be obtained from indolic N -hydroxylamines (Xj) , ( X k) and (XI) respectively according to the procedure described in this patent.
- the compound (Zi) can be obtained from indolic N -hydroxylamine (Yi) according to the procedure described in this patent.
- the compounds (Zk) and (Zl) can be obtained from indolic N -hydroxylamines (Yk) and (Yl) respectively according to the procedure described in this patent.
- the compounds 2-4 were prepared from the corresponding 2-(1 H -indol-3-yl)-2-oxoacetyl chlorides (8a-c) and indolic primary amines (1a) and (1b) according the procedure described in the literature : X. Guinchard, Y. Vallée, J.-N. Denis, « Total syntheses of brominated marine sponge alkaloids » Org. Lett. 2007 , 9 , 3761-3764.
- the indolic primary amine (1a) (170 mg, 0.48 mmol) and triethylamine (77 mg, 0.768 mmol) were dissolved in 5 mL of dry dichloromethane and 1 mL of dry THF. After cooling this solution to 0 °C, the acid chloride (8b) (165 mg, 0.576 mmol) was added and the mixture was stirred at 0 °C for one hour. The reaction was then quenched with an aqueous saturated solution of NaHCO 3 and diluted with ethyl acetate. The organic layer was washed with saturated NaHCO 3 and water, dried over anhydrous MgSO 4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 7/3) to afford the desired product 4 (180 mg, 0.30 mmol) as a white solid. Yield: 62 %.
- nicotinic acid (492 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 °C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The solid was washed with pentane and dried under vacuum. The desired nicotinoyl chloride hydrochloride was obtained as a white solid and used straightaway.
- a cold solution of hydrochloric acid was prepared by reaction of freshly distilled acetyl chloride (0.714 ml, 785 mg, 10.0 mmol) with 5 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was added to a solution of both nitrone 9a-c (5.0 mmol) and indole (aa or ab) (5.0 mmol) in 15 mL of dry methanol and 50 ml of dry dichloromethane. The reaction mixture was stirred at 0 °C during 2 hours to completion. A saturated aqueous solution of NaHCO 3 was then added. The mixture was extracted with dichloromethane (3x20 mL) and the collected organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum.
- the compound 10a (840 mg, 3.89 mmol) was obtained from piperidine (425 mg, 5.0 mmol) and indole (aa) (585 mg, 5.0 mmol). Yield: 78%.
- the compound 10c (1.208 g, 3.81 mmol) was obtained from N-Boc-piperazine (930 mg, 5.0 mmol) and indole (aa) (585 mg, 5.0 mmol). Yield: 76%.
- the compound 10d (915 mg, 3.10 mmol) was obtained from piperidine (425 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 62%.
- the compound 10e (1.13 g, 3.79 mmol) was obtained from morpholine (435 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 76%.
- the compound 10f (1.03 g, 2.61 mmol) was obtained from (N-Boc)piperazine (930 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 52%.
- the compound 11a (200 mg, 1 mmol) was obtained from N -hydroxylamine 10a (216 mg, 1.0 mmol). Yield: 100%.
- indolic amine 11a-f 1.0 mmol
- indolic oxoacetyl chloride (8a) or (8b) 1.2 mmol
- the resulting mixture was stirred at room temperature during 1 hour.
- a saturated aqueous solution of NaHCO 3 was then added.
- the mixture was extracted with EtOAc (3x20 mL) and the collected organic layers were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under vacuum.
- the compound 6a (205 mg, 0.55 mmol) was obtained from amine 11a (200 mg, 1.0 mmol) and oxoacetyl chloride (8a) (249 mg, 1.2 mmol). Yield: 55%.
- a cold solution of hydrochloric acid was prepared by reaction of freshly distilled acetyl chloride (0.143 mL, 157 mg, 2.0 mmol) with 3 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was then added to a solution of bis-indole 6f (126 mg, 0.2 mmol) in 2 mL of dry methanol. The resulting mixture was stirred during 2 hours at room temperature. Methanol was then slowly evaporated under vacuum (t ⁇ 20°C) till 1 mL. The saturated solution then was added dropwise to 50 mL of ether and the solid precipitate was filtered off and dried under vacuum. The bis-indolic amine salt 7 (80 mg, 0.14 mmol) was obtained as a rose-grey solid. Yield: 71%.
- Bacterial inocula were prepared in Mueller Hinton broth (MH2, bioMérieux, Marcy L'Etoile, France), supplemented with 10% sheep blood for fastidious species (i.e., Streptococcus pneumoniae and Haemophilus influenzae ). They were dispensed in 96 well microtiter plates (5 x 10 5 CFU/ml of final inoculum). Indolic compounds were added to the wells as to obtain two-fold serial concentrations (0.25-64 mg/L of final concentrations). Plates were incubated at 37 °C in ambient air, or at 37 °C in 5% CO 2 enriched atmosphere for fastidious species.
- MICs were read after 18 hours incubation of cultures, and corresponded to the minimum indolic compound concentration that allowed complete visual growth inhibition of bacteria.
- Drug-free cultures served as growth controls.
- Cultures receiving gentamicin, ciprofloxacin or cefotaxime served as positive controls.
- compounds of the invention present an anti-Staphylococcus activity even against strains presenting an acquired resistance to beta-lactams, including methicillin-resistant Staphylococcus aureus (MRSA) strains such as CIP65.25 (MetiR) and ATCC 33592 (MetiR), and/or to glycopeptides such as the VISA (vancomycin-intermediate S . aureus ) strain ATCC 106414.
- MRSA methicillin-resistant Staphylococcus aureus
- VISA vancomycin-intermediate S . aureus
- aureus ATCC 9144 >128 4 0.8 1 >128 >128 >128 >128 >128 >32 >128 >128 S .
- aureus ATCC 6538 >128 4 0.8 1 >128 >128 >128 >128 >128 >32 64 128 S .
- aureus CIP 65.6 >128 4 0.8 2 >128 >128 >128 >128 >128 >128 >32 >128 128 S .
- aureus CIP 103428 >128 4 1.6 1 >128 >128 >128 >128 >128 >128 >128 >32 64 128 S.
- aureus CIP 65.25 (MetiR) >128 4 1.6 1 >128 >128 >128 >128 >128 >32 >128 128 S.
- aureus ATCC 33592 (MetiR) >128 4 0.8 1 >128 >128 >128 >128 >128 >32 >128 128 S.
- aureus ATCC 106414 (VISA) >128 4 0.8 1 >128 >128 >128 >128 >128 >128 >128 >32 >128 128 S.
- epidermidis CIP 81.55 >128 8 1.6 2 >128 >128 >128 >128 >128 >32 >128 >128 S.
- the MBC was determined using a macro-method. Sterile tubes were filled with a primary bacterial inoculum prepared in Mueller Hinton broth as above (10 6 CFU/mL of final inoculum) and indolic compounds were added at twofold serial concentrations (0.25-64 mg/L of final concentrations). After 18 hours incubation of cultures, ten-fold serial dilutions of the cultures with no visible bacterial growth were prepared, and 100 ⁇ l of each dilution were inoculated to Mueller Hinton agar media for 24-48 hours. CFU counts were then determined and the MBC corresponded to the minimal indolic compound concentration for which 99.9% of more bacterial cells were killed after 18 hours of incubation.
- Killing curves corresponded to the measure of the kinetic of bactericidal activity of indolic compounds over time (time-kill curves) or after 18h incubation of cultures according to different drug concentrations (concentration-killing curves).
- Sterile tubes were inoculated with : 1/ sterile Mueller Hinton broth, to serve as negative control ; 2/ a drug-free bacterial inoculum, to serve as a growth control; 3/ a bacterial inoculum (10 5 CFU/ml of final concentration) with various concentrations of the tested indolic compound. The tubes were incubated at 37 °C with agitation (50 rpm).
- Bacterial inocula are determined in each tube using the CFU count method at the beginning of the experiments, and then after 18h for concentration-killing curves, or after 1h, 2h, 4h, 8h and 18h for time-kill curves.
- a significant bactericidal effect corresponds to reduction of the initial bacterial load of 3 logs or more at any time of incubation.
- the mutation frequency is the number of individuals in a population with a particular mutation.
- the mutation frequency was determined for a specific bacterial species and a specific indolic compound.
- Mueller Hinton agar plates containing various indolic compound concentrations, i.e., MIC x 2, MIC x 4, MIC x 8, and MIC x 16 were prepared. These plates were inoculated with various bacterial suspensions: 10 7 , 10 8 or 10 9 UFC/ml. After 24 hours incubation of media at 37 °C, CFU were numerated.
- the mutation frequency corresponded to the ratio of resistant mutants counted on a specific plate to the CFU count of the primary inoculum, expressed as a percentage.
- the mutation frequency was determined for S. aureus ATCC 25923 strain.
- In vitro mutant strains that resisted to the most active indolic compounds were selected.
- a bacterial inoculum (5 x 10 4 CFU/mL) was prepared in Mueller Hinton broth and dispensed in a 24-well microtiter plate (1 ml per well). Each row received two-fold serial concentrations of the tested indolic compound (1/2 to 16 times the MIC of the wild-type strain). Plates were incubated 72-96 hours, and bacterial growth obtained in the well with the highest indolic compound concentration were harvested, diluted 1/40 and dispensed in a new 24-well microtiter plate with increased drug concentrations (1/2 to 16 times the new MIC). The procedure was repeated several fold until we obtained high-level resistant mutants. The final and intermediate resistant mutant populations were all kept frozen at -80 °C for later analysis.
- the efflux pump inhibition potential of the bis-indolic derivatives was tested using two steps. In a first step, the intrinsic antibacterial activity of the compounds was assayed against the following strains:
- indolic derivatives initially solubilised in DMSO at 10 mg/mL were dispensed in a 96-wells microplate by two fold serial dilutions in Muller-Hinton medium (MH, Bio Rad) using a Biomek 2000 (Beckman) handling robot. 100 ⁇ L of the bacterial inoculum (an overnight culture at 37 °C in 5 mL MH diluted 100-fold) was then added in each well. The total volume was 200 ⁇ L in each well and the final bacteria concentration 10 6 CFU/mL (CFU: colony forming unit). The highest final indolic derivative concentration was 128 mg/L.
- Efflux pump inhibition assays were then performed against resistant Staphylococcus aureus strains SA 1199B and SA K2378 for bis-indolic derivatives.
- a serial dilution method was used to test the bis-indolic compounds (maximal concentration 128 mg/L) in the presence of a sub-inhibitory concentration of the ciprofloxacin (4 mg/L, MIC/4 and 2 mg/L, MIC/8) or less for SA 1199B and ciprofloxacin (0.5 mg/L, MIC/4 and 0.25 mg/L, MIC/8) for SA K2378.
- the minimal inhibitory concentration (MIC) of the bis-indolic compound allowing a complete inhibition of the bacterial growth in the presence of ciprofloxacin was determined.
- Results are presented in table II: TABLE II Compounds CMI, mg/L (Ciprofloxacin concentration, mg/L) Staphylococcus aureus 1199B Staphylococcus aureus K2378 2 0.5 (4) - 2 (2) 6a ⁇ 0.125 (4) 8 (0.25) 6b 0.5 (4) 16 (0.25) 6c 0.25 (4) 16 (0.25) 6d ⁇ 0.125 (4) 8 (0.25) 6f ⁇ 0.25 (4) 1 (0.25) 1 (0.5)
- IC 50 are presented in table IV. TABLE III Compounds KB MRC5 HCT116 10 -5 M (10 -6 M) 10 -5 M (10-6 M) 10-5 M (10 -6 M) 2 97 ⁇ 1 (33 ⁇ 8) 100 ⁇ 2 (10 ⁇ 5) 96 ⁇ 1 (53 ⁇ 4) 3 100 ⁇ 1 (4 ⁇ 3) 98 ⁇ 1 (0 ⁇ 3) 97 ⁇ 1 (0 ⁇ 13) 4 76 ⁇ 5 (0 ⁇ 7) 51 ⁇ 9 (0 ⁇ 3) 58 ⁇ 4 (0 ⁇ 9) 5 91 ⁇ 3(0 ⁇ 11) 85 ⁇ 2 (6 ⁇ 3) 80 ⁇ 3 (10 ⁇ 6) 6a 20 ⁇ 13 (0 ⁇ 18) 28 ⁇ 9 (0 ⁇ 15) 37 ⁇ 6 (0 ⁇ 5) 6b 9 ⁇ 4 (0 ⁇ 8) 15 ⁇ 11 (0 ⁇ 3) 21 ⁇ 10 (2 ⁇ 13) 6c 66 ⁇ 8 (0 ⁇ 8) 6 ⁇ 16 (0 ⁇ 17) 53 ⁇ 3 (8 ⁇ 2) 6d 53 ⁇ 5 (0 ⁇ 19) 0 ⁇ 3 (0 ⁇ 26) 41 ⁇ 4 (4 ⁇ 13) 6e 29 ⁇ 6 (0 ⁇ 2) 0 ⁇ 10 (0 ⁇ 12) 24 ⁇ 6 (3 ⁇ 8) 6f 92 ⁇ 3 (0
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Abstract
Description
- The present invention relates to novel bis-indolic derivatives, processes for their preparation, and their potential use as new antibacterial drugs.
- Penicillin G was the first natural antibiotic identified, first by Ernst Duchesne in the 19th century, then rediscovered in 1928 by Alexander Fleming.
- Sulfonamides, synthetic antibiotics, have emerged at the same time as penicillin G. Prontosil was the first compound of this class to be synthesized in 1932 by Gerhard Domagk. However, the sulfamidotherapy only began after J. and TH. Trefouël, F. Nitti and D. Bovet discovered in 1935 that prontosil was metabolized in the active compound sulfanilamide.
- Most of the major classes of natural antibiotics have been isolated and characterized between 1940 and 1960. The quinolones, synthetic antibiotics, were introduced in 1962. Then, it was only 40 years later, in 2000, that a novel class of synthetic antibiotics was discovered: the oxazolidinone class.
- Despite the discovery of numerous active compounds, their medical interest has been more or less quickly reduced because of development of bacterial resistances. Resistance mechanisms include the inactivation of the drug by specific enzymes, alteration of the antibiotic target, bacterial wall impermeability to antibiotic entry, and efflux of the antibiotic from the bacterial cytosol. These mechanisms usually develop within a few years after a new drug is introduced into clinical practice.
- To overcome the problem of antibiotic resistance, three ways can be considered:
- 1) structural modifications of existing drugs to obtain new compounds with maintained activity in the presence of known resistance mechanisms
- 2) restoration of the activity of existing antibiotics by combining a compound that inhibits bacterial resistance mechanisms and
- 3) development of novel antibiotic classes with original chemical structures and modes of action, as to avoid the deleterious effect of previously selected antibiotic resistance mechanisms, these new antibiotics will thus be effective against major antibiotic-resistant human pathogens.
- As an example, Staphylococcus aureus (a major human pathogen) may resist to antibiotics by the production of enzymes (e.g., penicillinase leading to resistance to penicillin G, transferases leading to resistance to aminoglycosides), by the modification of natural targets (e.g., acquisition of mecA gene in methicillin-resistant strains), or by efflux systems (e.g., NorA and fluoroquinolone resistance).
- Because the dramatic increase in antibiotic resistances became a public health problem, the pharmaceutical industry relaunched at the beginning of the 1990's the research on antibacterial compounds. This led to the linezolide success (Y. Van Laethem, J. Sternon Rev. Med. Brux. 2004, 25, 47-50), oxazolidinones development by Pfizer, and daptomycin development by Novartis (F. P. Tally, M. F. DeBruin, « Development of daptomycin for Gram-positive infections », Journal of Antimicrobial Chemotherapy, 2000, 46, 523-526 ; L. Robbel, M. A. Marahiel « Daptomycin, a bacterial lipopeptide synthesized by a nonribosomal machinery » J. Biol. Chem. 2010, 285, 27501-27508).
- Since 2000, oxazolidinones and cyclic lipopeptides have been the two only new antibiotic classes with a complete original structure approved in the treatment of Gram-positive bacterial infections. Linezolide and daptomycin are the only commercialized compounds of the oxazolidinone and lipopeptide classes, respectively. Their antibacterial spectrum comprises most of Gram-positive bacteria responsible for human infections, including multi-drug resistant strains such as the vancomycin-resistant Enterococcus sp. (VRE) and methicillin-resistant Staphylococcus aureus (MRSA).
- Other new antibiotics with a known structural moiety have been recently commercialized or are currently under development (V. Cattoir, C. Daurel, « Medecine et Maladies infectieuses », 2010, 40, 135-154) such as tigecycline, first glycylcycline that is a new class of hemi synthetic antibiotics derived from the tetracycline family (L. R. Peterson, « A review of tigecycline - the first glycylcyline », Int. J. Antimicrob. Agents, 2008, 32, S215-222). Tigecycline has a broad antibacterial spectrum comprising aerobic or anaerobic, Gram-positive or Gram-negative bacteria.
- Among β-lactams, new carbapenems have been developed. They have a broad antibacterial spectrum because of greater stability to the action of most β-lactamases. Three carbapenems are currently commercialized: imipenem, meropenem and ertapenem. A fourth one, doripenem, is close to the commercialization (M. Wolff, M.-L. Joly-Guillou, O. Pajot, « Les carbapénèmes », Réanimation, 2009, 18, 5199-5208). Their antibacterial spectrum encompasses most of aerobic and anaerobic bacteria. However, they are not effective against multi-drug resistant bacteria such as MRSA, methicillin-resistant coagulase-negative staphylococci, penicillin-resistant E. faecium, carbapenemase-producing Enterobacteraceae or Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.
- Two new cephalosporins (ceftobiprole and ceftaroline) with a broad antibacterial spectrum and an activity against MRSA are currently in phase III clinical trial.
- Pharmacokinetic parameters of vancomycin (lead of glycopeptides) and its relative toxicity have always been a hindrance to its intensive clinical use. Many endeavors have been accomplished to optimize its structure and this work has recently led to the development of the lipopeptides. Structurally close to the glycopeptide family, these compounds have a lipophilic chain added to the glycopeptide moiety (M. T. Guskey, B. T. Tsuji, « A comparative review of the lipoglycopeptides: oritavancin, dalbavancin, and telavancin », Pharmacotherapy 2010, 30, 80-94). Among these three compounds, telavancin is the only compound to be commercialized, the two others being still in phase II clinical trials.
- All these new compounds, except oxazolidinones and lipopeptides, present a structure derived from a molecule with a biosynthetized active moiety. This may facilitate rapid development by bacteria of resistance mechanisms to these new compounds. In addition, most of these new molecules have very complex structures, leading the big pharmaceutical company to hesitate to invest in this medicinal domain because the earning potential is unpredictable and could be even null in case of a fast apparition of resistance.
- There is thus an urgent need to develop new compounds that may help solving the problem of bacterial resistance to currently available antibiotics. This may be obtained by developing new classes of antibacterial agents with original structures and modes of action, and thus able to maintain their activity against microorganisms harboring known resistance mechanisms. Ideally, the newer compounds may prevent or delay the emergence of new resistance mechanisms leading to their inactivation. Another solution will consist in developing molecules liable to block existing bacterial resistance mechanisms, in order to restore the activity of currently available antibiotics.
- Recently, a new class of molecules showing antimicrobial activity named indole derivatives has been disclosed in the international application
WO 2008110690 . However, the minimum inhibitory concentrations (MIC) obtained for various bacterial species, especially multi-drug resistant bacteria, are relatively high. - One objective of the present invention is to provide new compounds, with new structures, and an improved antibacterial activity as compared to monoindole derivatives, including against bacteria resistant to multiple antibiotics.
- Another aim of the invention is to provide new compounds with an original structure liable to inhibit the NorA efflux pump of Staphylococcus aureus, responsible for fluoroquinolone resistance in this species.
- Another aim of the invention is to provide new compounds having both an antibiotic activity when used alone or in association with fluoroquinolones, and a NorA efflux pump inhibition activity.
- Still another aim is to provide pharmaceutical compositions comprising said new compounds.
-
- X and X' represent independently from each other O or S, and
- a) R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4 and R'5 represent independently from each other:
- H,
- a linear or branched (C1-C7)alkyl, if appropriate substituted by: a halogen, a hydroxyl group, a ORa or NRaRb, wherein Ra and Rb represent: H, a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group
- a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group,
- F, Cl, Br, I, CF3, OH, ORa, OCF3, COCF3, NH2, NHRa, NRaRb, wherein Ra and Rb represent:
H, a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group, - CN and NO2 provided that R1, R2, R3, R4, R5, R'1 are different from CN and NO2.
- (CH2)n-Z, -(CH2)n-OH, -(CH2)n-CO2-(C1-C7)-alkyl, -(CH2)n-CO2H wherein n = 2 to 12, Z is a halogen and alkyl being as defined above,
R represents H, a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CH2NHCO2-(C3-C7)-cycloalkyl, CO2H, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(C1-C7)-alkyl, CONH-(C3-C7)-cycloalkyl, CONH-aryl, CONH-(CH2)nOH, CONH-(CH2)nNRaRb, wherein n = 2 to 12 and Ra, Rb, aryl and alkyl being as defined above,
R6 and R'6 represent independently from each other H, (C1-C7)-alkyl, SO2aryl, wherein aryl being as defined above, OH, O-(C1-C7)-alkyl, CO-(C1-C7)-alkyl, CO-aryl, CH2NH2, CH2NHRa, CH2NaRb, Si(Rc)3, the Rc groups being identical or different and representing independently of each other a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, or an aryl, aryl and alkyl being as defined above,
R7 represents H, OH, ORa, Ra being as defined above,
or
- b) R and R7 are joined together to form a cycle of formula I-a:
- N-R8 wherein R8 represents H, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, CO-(C1-C7)-alkyl, CO-(C3-C7)-cycloalkyl, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl,
- O,
- S,
- CH2, CHR8 wherein R8 represents (C1-C7)-alkyl, (C3-C7)-cycloalkyl, CO-(C1-C7)-alkyl, CO-(C3-C7)-cycloalkyl, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl,
- m = 0, 1
R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4, R'5, R6 and R'6 being as defined above,
or - c) R and R7 are joined together to form a cycle of formula I-b:
- CH, CR8 wherein R8 represents (C1-C7)-alkyl, (C3-C7)-cycloalkyl, CO-(C1-C7)-alkyl, CO-(C3-C7)-cycloalkyl, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl,
- m = 1 R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4, R'5, R6 and R'6 being as defined above,
for use as a medicament, suitable especially for an antibacterial activity and/or NorA efflux pump inhibitor. - a) R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4 and R'5 represent independently from each other:
- By linear alkyl group from C1 to C7 is meant a group such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.
- By branched alkyl group is meant an alkyl group as defined above bearing substituents selected from the list of linear alkyl groups defined above, said linear alkyl group being also liable to be branched.
- Both linear and branched alkyl definitions apply to the entire specification.
- By cycloalkyl group from C3 to C7 is meant a group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Such groups can also be substituted by a linear or branched alkyl group as defined above.
- The definition of cycloalkyl group applies also to the entire specification.
- The term "aryl" refers to any functional group or substituent derived from a simple aromatic ring.
- The aryl can be substituted by one or more groups chosen independently among an halogen, a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, CN, CF3, OH, ORx, NH2, NHRx, NRxRy, Rx and Ry being a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl or cycloalkyl, CO-aryl, CO2H, CO2-(C1-C7)-alkyl or cycloalkyl,
- The term "heteroaromatic" refers to a compound having the characteristics of an aromatic compound whilst having at least one non-carbon atom in the ring.
- The heteroaromatic can be substituted by one or more groups chosen independently among those defined for aryl.
- In formula I-a, if m = 0, then the cycle is constituted of five atoms, if m = 1, the cycle is constituted of six atoms.
- In formula I-b, if m = 1, then the cycle is constituted of six atoms.
- A basic group such as the nitrogen of the indole moiety or an amino group present on the molecule can be under a salt form, the salt being any pharmaceutically acceptable salt obtained by reaction of an inorganic acid, an organic acid or a halogenoalkyl, on an amino group to give a quaternary ammonium.
- Examples of inorganic acid allowing obtaining pharmaceutically acceptable salts include, without being limited to them, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, formic acid, monohydrogenocarbonic acid, phosphoric acid, monohydrogenophosphoric acid, dihydrogenophosphoric acid, perchloric acid, sulfuric acid, monohydrogenosulfuric acid.
- Examples of organic acid allowing obtaining pharmaceutically acceptable salts include, without being limited to them, acetic acid, lactic acid, propionic acid, butyric acid, isobutyric acid, palmitic acid, malic acid, glutamic acid, hydroxymalic acid, malonic acid, benzoic acid, succinic acid, glycolic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, salicylic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydroxynaphthoic acid.
- As the molecule can also bear an acid group, and as at least one substituent of the indole moiety or of the aryl or heteroaromatic groups can be a phenol, they can also be under a pharmaceutically acceptable salt form.
- The salt can be obtained with organic or mineral bases, to give for instance alkali metal salts such as, lithium, sodium, potassium salts.
- As an example, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19.
- When R is different from H, the molecule presents an asymmetric carbon and thus compounds of the invention can be the R or the S enantiomer, a racemic mixture of both enantiomers or a mixture comprising 0.01%-99.99% of the R enantiomer and 99.99%-0.01% of the S enantiomer.
- The inventors have found that some compounds bearing two indole moieties, present an antibiotic activity on bacteria, and said compounds presenting an original structure with regards to all existing antibiotics; they are promising candidate not to develop a resistance or to develop only late resistance.
- The finding of the inventors is that compounds lacking the indole moiety borne by the carbonyl group of the keto-amide function lose completely the antibiotic activity (see comparative examples).
- The inventors have also found that some compounds are NorA efflux pump inhibitor and thus could be used in association with known antibiotics allowing reversing the antibiotic resistance toward said antibiotics.
- Further, compounds of the invention present also both intrinsic antibacterial activity and NorA efflux pump inhibitor activity.
- In an advantageous embodiment, the present invention relates to compounds defined above, wherein:
- X and X' are as defined above,
- R1, R2, R3, R4, Rs, R6, R'1, R'2, R'3, R'4, R'5 and R'6 are as defined above,
- R represents H, a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CH2NHCO2-(C3-C7)-cycloalkyl, CO2H, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(C1-C7)-alkyl, CONH-(C3-C7)-cycloalkyl, CONH-aryl, CONH-(CH2)nOH, CONH-(CH2)nNRaRb, wherein n = 2 to 12 and Ra, Rb, aryl and alkyl being as defined above.
- R7 represents H, OH, ORa, Ra being as defined above.
- In this embodiment, compounds of the invention are compounds wherein R and R7 are not joined and presenting an antibacterial activity and/or NorA efflux pump inhibitor.
- In an advantageous embodiment, the present invention relates to compounds defined above, wherein:
- X and X' are as defined above,
- R1, R2, R3, R4, R5, R6 R'1, R'2, R'3, R'4, R'5 and R'6 are as defined above, and
- R and R7 are joined together to form a cycle of formulas I-a and I-b as defined above.
- In this embodiment, compounds of the invention are cyclic compounds presenting an antibacterial activity and/or NorA efflux pump inhibitor.
- In an advantageous embodiment, the present invention relates to compounds defined above, wherein the antibacterial activity is against Gram-positive and Gram-negative bacteria.
- Another advantage of the invention is to provide antibiotics active both against Gram-positive and Gram-negative bacteria.
- The term "Gram-positive bacteria" refers to the two bacterial phyla defined in the Bergey's manual of systematic bacteriology (2nd edition, G. M. Garrity (ed.), Springer, 2005), Actinobacteria, and Firmicutes, and include the well known genera Staphylococcus, Streptococcus; Enterococcus, Listeria and Bacillus,
- The term "Gram-negative bacteria" refers to 22 bacterial phyla defined in the Bergey's manual of systematic bacteriology (2nd edition, G. M. Garrity, Springer, 2005), Aquificae, Thermotogae, Thermodesulfobacteria, Deinococcus-Thermus, Chrysiogenetes, Chloroflexi, Thermomicrobia, Nitrospira, Deferribacteres, Cyanobacteria, Chlorobia, Proteobacteria, Planctomycetes, Chlamydiae, Spirochaetes, Fibrobacteres, Acidobacteres, Bacteroidetes, ,Fusobacteria, Verrucomicrobia, Dictyoglomi, and Gemmatimonadetes.
- Proteobacteria, in particular, include a large number of human pathogens such as the Enterobacteriaceae, Pseudomonadaceae, Vibrionaceae, Moraxellaceae, Neisseriaceae and Pasteurellaceae families.
- In an advantageous embodiment, the present invention relates to compounds of formula I defined above, wherein said compounds are narrow spectrum antibiotics having the advantage not to alter the intestinal microbiota.
- By the expression "narrow-spectrum" it must be understood that compounds of the invention are able to act as an antibiotic effective against only specific families of bacteria (in the invention Gram-positive Staphylococcus aureus and coagulase-negative Staphylococcus species, and to a lesser extent Gram-positive Streptococcus and Bacillus species and Gram-negative Haemophilus species).
- This is in contrast to a broad-spectrum antibiotic which is effective against a wide range of disease-causing bacteria.
- In an advantageous embodiment, the present invention relates to compounds defined above, wherein said bacteria are resistant to conventional antibiotics.
- Compounds of the invention are not only active against sensitive bacteria but also present the advantage to be active against bacteria resistant to currently available antibiotics.
- In an advantageous embodiment, the present invention relates to compounds defined above, wherein the antibacterial activity is against Staphylococcus species, in particular Staphylococcus aureus, especially Staphylococcus aureus resistant to β-lactams (including methicillin-resistant strains, also referred as MRSA), Staphylococcus aureus resistant to glycopeptides (vancomycin-resistant or glycopeptides-resistant strains, also referred as VISA or GISA) and Staphylococcus aureus resistant to fluoroquinolones.
- Compounds of the invention are also active against coagulase-negative Staphylococcus species such as Staphylococcus epidermidis, including strains resistant to β-lactam or fluoroquinolone antibiotics.
- Compounds of the invention also present the advantage to be active against bacteria that are multi-resistant, i.e., resistant to several classes of antibiotics including those cited above.
- In an advantageous embodiment, the present invention relates to compounds defined above, having further an antifungal and/or antiviral activity.
- A further advantage of the compounds of the invention is that they present not only an antibacterial activity but also an antifungal activity or an antiviral activity. Some of the compounds also present the triple activity.
-
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
-
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
-
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II wherein R6 and R'6 represent H.
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II wherein R2, R5, R'2 and R'5 represent H.
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II wherein R7 represent H.
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II, wherein R6 and R'6 are different.
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II, wherein R1 is different from R'1 and/or R2 is different from R'2, and/or R3 is different from R'3 and/or R4 is different from R'4 and/or R5 is different from R'5.
- In this embodiment, R and R7 are not joined together to form a cycle of formula I-a or I-b.
- In an advantageous embodiment, the present invention relates to compounds defined above, having the formula I or II, wherein R1 is similar to R'1, and/or R2 is similar to R'2, and/or R3 is similar to R'3, and/or R4 is similar to R'4, and/or R5 is similar to R'5 and/or R6 is similar to R'6.
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
-
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
-
- In this embodiment, R and R7 are not joined together and do not form a cycle of formula I-a or I-b.
-
- R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I,
- R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
- In an advantageous embodiment, the present invention relates to compounds of formula V defined above, wherein:
- R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I, at least one of
- R3, R4, R'3 and R'4 represents F, Cl, Br, I,
- R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
- Preferably at least one halogen atom must be present in R3, R4, R'3 or R'4 position, more preferably two halogens atoms (one halogen atom on each indole cycle) must be present and more preferably said halogen is Br.
- It has been found by the inventors that compounds of formula V bearing at least one halogen atom on at least one of the two indole moieties present an antibacterial activity.
- For compounds presenting an antibacterial activity as compounds of formula V for instance, the determination of the NorA efflux pump inhibition activity is possible only with specific techniques.
- Therefore, such compounds are either only antibiotics or present both activities.
-
- R3 and R'3 represent independently from each other H, F, Cl, Br, I, at least one of R3 and R'3, represents F, Cl, Br, I,
- R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
-
-
- R4 and R'4 represent independently from each other H, F, Cl, Br, I, at least one of R4 and R'4 represents F, Cl, Br, I,
- R represents a (C1-C7)-alkyl, CH2NHCO2(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
-
-
- R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
-
- It has been found by the inventors that compounds of formula V-1 bearing no halogen atom on the two indole moieties present no antibacterial activity but present a NorA efflux pump inhibition activity.
- One of the advantages of the compounds of the invention having a NorA efflux pump inhibition activity is the possibility of said compounds to reverse the resistance of a bacterial strain that became resistant to a classical antibiotic if they are administered with said classical antibiotic provided that classical antibiotic and compounds of the invention belong to different families of antibiotics.
-
- Y = N-R8, R8 being NBoc or NH,
- Y = CH2, CH-R8, R8 being as defined above,
- R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I,
- m = 0 or 1.
- It has been found by the inventors that compounds of formula VIII do not need the presence of at least one halogen atom on at least one of the two indole moieties to show an antibacterial activity or a NorA efflux pump inhibition activity.
- For compounds of formula VIII presenting an antibacterial activity, the determination of the NorA efflux pump inhibition activity is possible only with specific techniques.
- Therefore, such compounds are either only antibiotics or present both activities.
-
-
- Y = CH, C-R8, R8 being as defined above,
- R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I,
- m = 1.
- In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I, in association with a pharmaceutically acceptable vehicle.
- The expression "pharmaceutically acceptable vehicle" denotes in particular cellulose, starch, benzyl alcohol, polyethylene glycol, gelatin, lactose, polysorbate, magnesium or calcium stearate, xanthan gum, guar, alginate, colloidal silica.
- The compositions according to the invention can be used by oral, parenteral, topic, or rectal route or in aerosols.
- As solid compositions for oral administration, tablets, pills, gelatin capsules, powders or granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents or adjuvants, such as saccharose, lactose or starch. These compositions can comprise substances other than the diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.
- As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also comprise substances other than the diluents, for example wetting products, sweeteners or flavourings.
- The compositions for parenteral administration can be sterile solutions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate can be used. These compositions can also contain adjuvants, in particular wetting agents, isotoning agents, emulsifiers, dispersants and stabilizers.
- The sterilization can be carried out in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the moment of use in sterile water or any other injectable sterile medium.
- The compositions for topical administration can be for example creams, ointments, lotions or aerosols.
- The compositions for rectal administration are suppositories or rectal capsules, which, in addition to the active ingredient, contain excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
- The compositions can also be aerosols.
- For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the moment of use in pyrogen-free sterile water, in serum or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active ingredient is finely divided and combined with a diluent or hydrosoluble solid vehicle, for example dextran, mannitol or lactose.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, administrable by oral route at a dose comprised from about 10 mg/kg to about 200 mg/kg.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, under a form liable to be administrable by oral route at a dose comprised from 100 mg to 1,500 mg, in particular from 100 mg to 1,000 mg, in particular from 100 to 500 mg.
- Said pharmaceutical composition can be administered 2 or 3 times per day.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, administrable by intraveinous route at a dose comprised from about 5 µg/kg to about 50 mg/kg.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, under a form liable to be administrable by intraveinous route at a dose comprised from 0,1 mg to 1000 mg, in particular from 10 mg to 1,000 mg, in particular from 10 to 500 mg, in particular from 10 to 100 mg.
- Said pharmaceutical composition can be administered 2 or 3 times per day.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula V.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VI, such as compounds 4 or 5.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VII, such as compound 3.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula V-1, such as compound 2.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising a compound of the formula VIII, such as compounds 6a, 6b, 6c, 6d, 6e, 6f or 7.
- In an advantageous embodiment, the present invention relates to a pharmaceutical composition defined above, comprising further:
- at least one antibiotic compound, in particular from the fluoroquinolones family, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin or moxifloxacin, said pharmaceutical composition being used for simultaneous or separate use or use spread over time intended for the treatment of pathologies associated with bacterial infections for which a resistance to the antibiotic, in particular from the fluoroquinolones family exists.
- Said antibiotic compound must be from a different family of the one of the compounds of the invention.
- In this embodiment, if a compound of the invention is a NorA efflux pump inhibitor, administration of said compound with an antibiotic for which the bacterium is resistant allows to restore the antibiotic activity against bacteria that became resistant to said antibiotic.
- If the compound of the invention presents only an antibacterial activity, administration of said compound with another antibiotic allows having a broader spectrum or increased activity.
-
- Compounds 9, 10 and 11
9a : X = CH2; 9b: X = O ; 9c: X = NBoc
10a : X = CH2 and R = H; 10b: X = O and R = H ; 10c: X = NBoc and R = H
10d : X = CH2 and R = Br; 10e: X = O and R = Br; 10f: X = NBoc and R = Br
11a : X = CH2 and R = H ; 11b : X = O and R = H; 11e : X = NBoc and R = H
11d : X = CH2 and R = Br; 11e: X = O and R = Br; 11f : X = NBoc and R = Br
- The 2-(1H-indol-3-yl)-2-oxoacetyl chlorides (8a) and (8c) were prepared according the procedure described in the literature. See : X. Guinchard, Y. Vallée, J.-N. Denis, « Total synthesis of marine sponge bis(indole) alkaloids of the topsentin class », J. Org. Chem. 2007, 72, 3972-3975 ; X. Guinchard, Y. Vallée, J.-N. Denis, « Total syntheses of brominated marine sponge alkaloids », Org. Lett. 2007, 9, 3761-3764.
- Commercially available:
- Sigma-Aldrich P O Box 14508 St. Louis, MO 63178 USA
or - Alfa Aesar A Johnson Matthey Company
- Shore Road Port of Heysham Industrial Park Heysham, Lancashire, LA3 2XY United Kingdom Phone: 0800 801812
- To a solution of indole (468 mg, 4.0 mmol) in anhydrous diethyl ether (10 mL) at 0 °C, freshly distilled oxalyl chloride (0.418 mL, 609 mg, 4.8 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1.5 h and then allowed to warm to room temperature during an additional hour. After evaporation under vacuum, the resulting solid was collected by filtration, triturated in cold anhydrous diethyl ether, washed twice with this solvent and dried under vacuum. The obtained yellow solid (8a) (764 mg, 3.68 mmol) was used without further purification. Yield: 92%.
- Commercially available:
- ASW MedChem, Inc. 100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- Under argon, a dry flask was charged with 5-bromoindole (ab) (400 mg, 2.04 mmol) and dry diethyl ether (5 mL). This solution was cooled to 0 °C and freshly distilled oxalyl chloride (0.210 mL, 2.45 mmol) was added. The solution was turned rapidly yellow. After stirring for 1h30 at 0 °C, the crude mixture was evaporated under reduced pressure. The resulting yellow solid was triturated and washed with dry diethyl ether and dried under vacuum. The desired product (8b) (524 mg, 1.83 mmol) was obtained as a yellow solid and was used after its preparation. Yield: 90%.
- Commercially available:
- ASW MedChem, Inc.100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- Under argon, a dry flask was charged with 6-bromoindole (ac) (400 mg, 2.04 mmol) and dry diethyl ether (5 mL). This solution was cooled to 0 °C and freshly distilled oxalyl chloride (0.210 mL, 2.45 mmol) was added. The solution was turned rapidly yellow. After stirring for 1h30 at 0 °C, the crude mixture was evaporated under reduced pressure. The resulting yellow solid was triturated and washed with dry diethyl ether and dried under vacuum. The desired product (8c) (479 mg, 1.67 mmol) was obtained as a yellow solid. Yield: 82%.
- Commercially available:
- ASW MedChem, Inc. 100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- The compound (8d) can be obtained from 5-chloroindole (ad) according to the procedure described in this patent.
- Commercially available:
- ASW MedChem, Inc. 100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- The compound (8e) can be obtained from 6-chloroindole (ae) according to the procedure described in this patent.
- Commercially available:
- ASW MedChem, Inc. 100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- The compound (8f) can be obtained from 5-fluoroindole (af) according to the procedure described in this patent.
- Commercially available:
- ASW MedChem, Inc.100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- The compound (8g) can be obtained from 6-fluoroindole (ag) according to the procedure described in this patent.
- 2-(5-Iodo-1H-indol-3-yl)-2-oxoacetyl chloride (8h)
- 2-(6-Iodo-1H-indol-3-yl)-2-oxoacetyl chloride (8i)
- 2-(7-Bromo-1H-indol-3-yl)-2-oxoacetyl chloride (8k)
- 2-(2-Bromo-1H-indol-3-yl)-2-oxoacetyl chloride (8l)
- The compounds (8h-i) and (k-I) can be obtained from indoles (ai-i) and (ak-I) according to the procedure described in this patent.
- 2-(4-Bromo-1H-indol-3-yl)-2-oxoacetyl chloride (8j)
- Commercially available:
- ASW MedChem, Inc. 100 Jersey Ave Box C-10 New Brunswick, NJ 08901 USA
- The compound (8j) can be obtained from 4-bromoindole (aj) according to the procedure described in this patent.
- A cold solution of hydrochloric acid was prepared by reaction of 1.12 mL (1.25 g, 15.91 mmol) of freshly distilled acetyl chloride with 40 mL of dry methanol. This solution was stirred at 0 °C during 15 min and then was added a mixture of both indole (aa) (0.93 g, 7.95 mmol) and nitrone (ea) (2.1 g, 7.95 mmol) in 20 mL of methanol. The reaction was stirred at 0 °C during 1 hour to completion. A saturated aqueous solution of NaHCO3 was then added. The mixture was extracted 3 times with CH2Cl2 and the collected organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The crude product was purified by trituration with pentane. The product (1a) was obtained as a white solid (3.0 g, 7.87 mmol). Yield: 99%.
- Mp: 145-146 °C. IR (neat): 3416, 3341, 3329, 3090, 3060, 3031, 2978, 2932, 2875, 2839, 1693, 1680, 1514, 1505, 1497, 1455, 1434, 1393, 1367, 1280, 1167, 1100 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.51 (s, 9H, C(CH3)3), 3.50-3.70 (m, 2H, CH2N), 3.75 (ABq, J AB = 14.4 Hz, δA-δB = 38.9 Hz, 2H, CH2Ph), 4.14 (t, J = 5.4 Hz, 1H, CHN), 4.88 (t, J = 6.5 Hz, 1H, NHBoc), 6.56 (s, 1H, OH), 7.08-7.39 (m, 9H, H arom), 7.66 (d, J = 7.5 Hz, 1H, H arom), 8.36 (s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.5 (C(CH3)3), 43.7 (CH2), 60.6 (CH2), 63.8 (CHN), 79.7 (C(CH3)3), 111.2 (CH arom), 112.3 (C arom), 119.6 (CH arom), 119.7 (CH arom), 122.2 (CH arom), 123.4 (CH arom), 126.7 (CH arom), 127.2 (C arom), 128.0 (CH arom), 128.6 (CH arom), 136.0 (C arom), 139.0 (C arom), 157.7 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z= 382 [(M+H)+]. Anal. calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02. Found: C, 69.23; H, 7.36; N, 10.77.
- A cold solution of hydrochloric acid was prepared by reaction of 0.143 mL (157 mg, 2.0 mmol) of freshly distilled acetyl chloride with 5 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was added to a mixture of both nitrone (ea) (1.0 mmol) and indole (aa-I) (1.0 mmol) in 5 mL of dry methanol. The reaction mixture was stirred at 0 °C during 2 hours to completion. A saturated aqueous solution of NaHCO3 was then added. The mixture was extracted with CH2Cl2 (3x10 mL) and the collected organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Purification of the resulting crude product by column chromatography using EtOAc-pentane (from 1/99 to 40/60) yielded pure product (Xb-I).
- The compound (Xb) (385 mg, 0.837 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 5-bromoindole (ab) (196 mg, 1.0 mmol) as a white solid. Yield: 84%.
- Mp: 170-171 °C. IR (neat): 3420, 3339, 2980, 2931, 1690, 1518, 1453, 1363, 1167 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.53 (s, 9H, C(CH3)3), 3.5-3.7 (m, 2H, CH2N), 3.7 (ABq, J AB = 13.7 Hz, δA-δB = 45.3 Hz, 2H, CH2Ph), 4.03 (t, J = 5.5 Hz, 1H, CHN), 4.87 (t, J = 6.9 Hz, 1H, NHBoc), 6.72 (s, 1H, OH), 7.15-7.35 (m, 8H, H arom), 7.84 (s, 1H, H arom), 8.37 (s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (C(CH3)3), 44.0 (CH2), 60.5 (CH2Ph), 63.9 (CHN), 80.0 (C(CH3)3), 112.7 (CH arom), 113.1 (C arom), 122.6 (CH arom), 123.2 (C arom), 124.6 (CH arom), 125.1 (CH arom), 126.8 (CH arom), 128.1 (CH arom), 128.6 (CH arom), 128.8 (C arom), 134.6 (C arom), 138.7 (C arom), 157.8 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 460 and 462 [(M+H)+]. Anal. calcd for C22H26N3O3Br: C, 57.40, H, 5.69, N, 9.13. Found: C, 57.07, H, 5.65, N, 9.22.
- The compound (Xc) (400 mg, 0.87 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 6-bromoindole (ac) (196 mg, 1.0 mmol) as a white solid. Yield: 87%.
- Mp: 150 °C. IR (neat): 3418, 3328, 3031, 2980, 2932, 1687, 1615, 1516, 1455, 1395, 1366, 1336, 1288, 1251, 1166, 1050, 1029, 897, 866, 846, 803, 738, 701 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.50 (s, 9H, C(CH3)3), 3.55-3.70 (m, 2H, CH2N), 3.72 (ABq, J AB = 14.0 Hz, δA-δB = 57.8 Hz, 2H, CH2Ph), 4.07 (t, J = 5.7 Hz, 1H, CHN), 4.78-4,91 (def. t, 1H, NHBoc), 6.52 (s, 1H, OH), 7.18-7.35 (m, 7H, H arom), 7.51-7.55 (m, 2H, H arom), 8.22 (s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (C(CH3)3), 43.9 (CH2), 60.5 (CH2), 63.2 (CHN), 79.9 (C(CH3)3), 112.2 (C arom), 114.2 (CH arom), 115.8 (CH arom), 120.9 (CH arom), 122.9 (CH arom), 124.1 (CH arom), 126.0 (C arom), 126.8 (CH arom), 128.1 (CH arom), 128.5 (CH arom), 136.7 (C arom), 138.8 (C arom), 157.7 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 460 and 462 [(M+H)+]. Anal. calcd for C22H26N3O3Br: C, 57.40; H, 5.69; N, 9.13. Found: C, 57.09; H, 5.87; N, 9.05.
- The compound (Xd) (360 mg, 0.867 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 5-chloroindole (ad) (152 mg, 1.0 mmol) as a white solid. Yield: 87%.
- IR (neat): 3315, 2970, 1655, 1520, 1295, 1165, 910, 895, 790, 735, 695 cm-1. 1H NMR (300 MHz, CDCl3-CD3OD): δ = 1.48 (s, 9H), 3.58-3.63 (m, 2H), 3.60 (d, J = 13.7 Hz, 1H), 3.81 (d, J = 13.7 Hz, 1H), 4.07 (t, J = 5.4 Hz, 1H), 5.37 (t, J = 6.2 Hz, 1H), 7.11 (dd, J = 2.0 and 8.6 Hz, 1H), 7.20-7.37 (m, 8H), 7.68 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 29.8 (3C), 45.3, 59.0, 63.7, 81.3, 113.9 (2 C), 120.7, 123.5 (2 C), 126.4 (2 C), 126.8, 128.4, 129.5 (2 C), 130.3, 136.4, 139.7, 158.0 ppm. LRMS (ESI): m/z (%) = 438 (22) [(M+Na)+], 416 (100) [(M+H)+], 293 (18), 237 (89), 193 (16).
- The compound (Xe) (340 mg, 0.819 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 6-chloroindole (ae) (152 mg, 1.0 mmol) as a white solid. Yield: 82%.
- IR (neat): 3405, 3360, 2975, 2850, 1655, 1520, 1455, 1365, 1290, 1160, 1105, 905, 800, 735, 695 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.50 (s, 9H), 3.54-3.63 (m, 2H), 3.62 (d, J = 14.0 Hz, 1H), 3.80 (d, J = 14.0 Hz, 1H), 4.07 (t, J = 5.6 Hz, 1H), 4.92 (t, J = 6.2 Hz, 1H), 6.52 (br s, 1H), 7.08 (dd, J = 1.7 and 8.5 Hz, 1H), 7.18-7.26 (m, 6H), 7.33 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 8.45 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.5 (3C), 43.7, 60.6, 64.7, 79.9, 111.2 (2 C), 120.4 (2 C), 120.5, 124.2, 125.7, 126.8, 128.1 (2 C), 128.6, 136.3, 138.7, 157.7 ppm. LRMS (ESI): m/z (%) = 438 (17) [(M+Na)+], 416 (97) [(M+H)+], 293 (17), 237 (100), 193 (9).
- The compound (Xf) (390 mg, 0.977 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 5-fluoroindole (af) (135 mg, 1.0 mmol) as a white solid. Yield: 98%.
- IR (neat): 3410, 3300, 2975, 2890, 1655, 1540, 1490, 1455, 1290, 1165, 935, 845, 745, 695 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.43 (s, 9H), 3.49-3.81 (m, 4H), 4.13 (t, J = 5.4 Hz, 1H), 6.90 (dt, J = 2.4 and 9.1 Hz, 1H), 7.20-7.40 (m, 8H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.8 (3C), 44.2, 60.9, 62.4, 78.2, 103.2 (d, J = 24.8 Hz), 110.6 (d, J = 26.4 Hz), 113.0 (d, J = 9.4 Hz), 124.3, 127.3, 127.8, 129.0 (2 C), 130.2 (2 C), 132.9, 136.7, 140.3, 156.7, 159.3 (d, J = 236.1 Hz). 19F NMR (282 MHz, CD3OD): δ = -124.2 (dt, J = 4.8 and 9.8 Hz, 1F) ppm. LRMS (ESI): m/z (%) = 422 (21) [(M+Na)+], 400 (97) [(M+H)+], 277 (17), 221 (100), 177 (20).
- The compound (Xg) (340 mg, 0.85 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 6-fluoroindole (ag) (135 mg, 1.0 mmol) as a white solid. Yield: 85%.
- IR (neat): 3410, 3365, 2975, 2875, 1655, 1625, 1520, 1290, 1165, 1140, 1095, 910, 830, 800, 735, 695 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.50 (s, 9H), 3.54-3.63 (m, 2H), 3.62 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 14.0 Hz, 1H), 4.08 (t, J = 5.7 Hz, 1H), 4.92 (t, J = 6.8 Hz, 1H), 6.50 (br s, 1H), 6.88 (dt, J = 2.3 and 9.4 Hz, 1H), 7.02 (dd, J = 2.0 and 9.6 Hz, 1H), 7.18-7.27 (m, 6H), 7.56 (dd, J = 5.3 and 8.7 Hz, 1H), 8.42 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.7 (3C), 44.0, 60.9, 64.0, 80.1, 97.7 (d, J = 26.2 Hz), 108.7 (d, J = 24.4 Hz), 120.7 (d, J = 10.4 Hz), 123.9, 124.0, 127.1, 128.3 (2 C), 128.8 (2 C), 132.3, 136.3, 138.9, 158.7, 160.3 (d, J = 238.1 Hz) ppm. 19F NMR (282 MHz, CDCl3): δ = -125.0 (dt, J = 4.7 and 9.6 Hz, 1F) ppm. LRMS (ESI): m/z (%) = 422 (58) [(M+Na)+], 400 (94) [(M+H)+], 277 (20), 221 (100), 173 (12).
- The compound (Xh) (420 mg, 0.828 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 5-iodoindole (ah) (243 mg, 1.0 mmol) as a white solid. Yield: 83%.
- IR (neat): 3315, 2960, 1660, 1525, 1455, 1390, 1365, 1295, 1165, 910, 880, 790, 740, 695 cm-1. 1H NMR (300 MHz, CDCl3-CD3OD): δ = 1.48 (s, 9H), 3.57-3.61 (m, 2H), 3.59 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 14.0 Hz, 1H), 4.07 (t, J = 5.8 Hz, 1H), 5.47 (br s, 1H), 7.18-7.30 (m, 7H), 7.41 (dd, J= 1.6 and 8.5 Hz, 1H), 8.03 (s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 29.9 (3C), 44.3, 59.1, 63.6, 84.2, 97.8, 115.1 (2 C), 123.7, 124.5, 126.4, 126.8, 128.2, 129.6 (2 C), 130.4, 131.5, 132.4, 134.9, 138.2, 157.5 ppm. LRMS (ESI): m/z (%) = 530 (33) [(M+Na)+], 508 (100) [(M+H)+], 329 (63).
- The compound (Xi) can be obtained from nitrone (ea) and 6-iodoindole (ai) according to the procedure described in this patent.
- The compound (Xj) (370 mg, 0.806 mmol) was obtained from nitrone (ea) (264 mg, 1.0 mmol) and 4-bromoindole (aj) (196 mg, 1.0 mmol) as a white solid. Yield: 81%.
- IR (neat): 3375, 3290, 2980, 2830, 1655, 1560, 1455, 1330, 1290, 1165, 1120, 910, 730, 695 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.43 (s, 9H), 3.51-3.69 (m, 2H), 3.69 (d, J = 14.3 Hz, 1H), 3.88 (d, J = 14.3 Hz, 1H), 5.29 (t, J = 6.0 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 7.19-7.31 (m, 6H), 7.42 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.9 (3C), 42.7, 62.2, 64.1, 80.2, 112.1, 114.3, 123.0, 125.1, 125.7, 126.6, 126.9, 127.3, 129.0 (2 C), 130.0, 132.8, 135.8, 138.9, 156.4 ppm. LRMS (ESI): m/z (%) = 482 (26) [(M+Na)+], 460 (100) [(M+H)+], 281 (37).
- The compound (Xk) can be obtained from nitrone (ea) and 7-bromoindole (ak) according to the procedure described in this patent.
- The compound (XI) can be obtained from nitrone (ea) and 2-bromoindole (al) according to the procedure described in this patent.
- A stirred solution of indolic N-hydroxylamine (Xa-I) (1 equivalent) in toluene was warmed to 100 °C. Five equivalents of manganese dioxide were added. The resulting heterogeneous mixture was then stirred at this temperature during 5-10 min. It was then cooled at room temperature and filtered on celite. Resulted heterogeneous solution was concentrated under vacuum. The obtained crude extract was purified by column chromatography on silica gel (previously treated by 2.5% of triethylamine) using EtOAc-pentane (from 5/95 to 90/10) affording pure product (Ya-I).
- The compound (Ya) (560 mg, 1.48 mmol) was obtained from indolic N-hydroxylamine (Xa) (724 mg, 1.9 mmol) and MnO2 (827 mg, 9.5 mmol) as a beige foam. Yield: 78%.
- Mp: 150 °C. IR (neat): 3302, 3056, 2979, 2927, 1699, 1686, 1505, 1460, 1369, 1253, 1176 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H, C(CH3)3), 3.78-3.95 (m, 1H, 1H of CH2), 3.95-4.10 (m, 1H, 1H of CH2), 5.49 (t, J = 5.9 Hz, 1H, CHN), 5.6-5.7 (br s, 1H, NHBoc), 7.11 (quint., J = 7.1 Hz, 2H, H arom), 7.22 (d, J = 2.0 Hz, 1H, H arom), 7.28 (d, J = 4.8 Hz, 1H, H arom), 7.33-7.40 (m, 3H, H arom), 7.57 (s, 1H, H arom), 7.70 (d, J = 7.0 Hz, 1H, H arom), 8.17- 8.24 (m, 2H, H ortho of Ph), 8.92 (s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (C(CH3)3), 42.9 (CH2), 71.9 (CHN), 79.7 (C(CH3)3), 109.8 (C arom), 111.6 (CH arom), 118.6 (CH arom), 120.1 (CH arom), 122.3 (CH arom), 124.1 (CH arom), 125.9 (C arom), 128,4 (CH arom), 128.8 (CH arom), 130.3 (C arom), 130.5 (CH arom), 134.9 (CH=N), 136.1 (C arom), 156.3 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 380 [(M+H)+], 279, 259, 258. HRMS (ESI) calcd for C22H25N3O3Na: 402.1794. Found: 402.1797 [(M+Na)+].
- The compound (Yb) (365 mg, 0.797 mmol) was obtained from indolic N-hydroxylamine (Xb) (575 mg, 1.25 mmol) and MnO2 (544 mg, 6.25 mmol) as a beige foam. Yield: 64%.
- Mp: 128 °C. IR (KBr): 3419, 3299, 3075, 2977, 2929, 1696, 1513, 1453, 1363, 1254, 1164, 887, 801 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9H, C(CH3)3), 3.72-3.83 (m, 1H, 1H of CH2N), 3.93-4.10 (m, 1H, 1H of CH2N), 5.39 (br s, 1H, NHBoc), 5.54 (br s, 1H, CHN), 6.99 (d, J = 8.6 Hz, 1H, H arom), 7.12 (dd, J = 1.7 and 8.6 Hz, 1H, H arom), 7.16 (d, J = 2.4 Hz, 1H, H arom), 7.30-7.45 (m, 3H, H arom), 7.61 (s, 1H, CH=N), 7.77 (d, J = 1.6 Hz, 1H, H arom), 8.15-8.30 (m, 2H, H arom), 9.57 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.5 ((CH3)3C), 43.0 (CH2N), 71.6 (CHN), 80.0 ((CH3)3 C), 109.3 (C arom), 113.3 (CH arom), 113.5 (C arom), 121.1 (CH arom), 125.3 (CH arom), 125.7 (CH arom), 127.8 (C arom), 128.7 (CH arom), 129.1 (CH arom), 130.2 (C arom), 131.0 (CH arom), 134.9 (C arom), 135.5 (CH=N), 156.5 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 458 and 460 [(M+H)+], 298 and 300, 281 and 283. HRMS (ESI) calcd for C22H24N3O3 79BrNa: 480.0899. Found: 480.0901 [(M+Na)+].
- The compound (Yc) (430 mg, 0.94 mmol) was obtained from indolic N-hydroxylamine (Xc) (598 mg, 1.30 mmol) and MnO2 (566 mg, 6.50 mmol) as a beige foam. Yield: 72%.
- Mp: 186 °C. IR (neat): 3276, 2979, 2934, 1699, 1505, 1460, 1369, 1253, 1169, 807, 691 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H, C(CH3)3), 3.70-3.80 (m, 1H, 1H of CH2), 3.80-4.10 (m, 1H, 1H of CH2), 5.40 (br s, 1H, CHN), 5.50-5.55 (m, 1H, NHBoc), 7.11-7.18 (m, 2H, H arom), 7.31 (d, J = 1,4 Hz, 1H, H arom), 7.37-7.43 (m, 3H, Ph), 7.53 (d, J = 8.4 Hz, 1H, H arom), 7.60 (s, 1H, H arom), 8.15-8.25 (m, 2H, 2 H ortho Ph), 9.37 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (C(CH3)3), 42.7 (CH2), 71.6 (CHN), 79.9 (C(CH3)3), 109.8 (C arom), 114.6 (CH arom), 115.8 (C arom), 119.8 (CH arom), 123.3 (CH arom), 128.6 (CH arom), 128.9 (CH arom), 130.0 (C arom), 130.9 (C arom), 135.5 (CH=N), 136.9 (C arom), 156.4 (C=O) ppm. LRMS (ESI): m/z = 480 and 482 [(M+Na)+], 458 and 460 [(M+H)+], 281 and 283. HRMS: (ESI) calcd for C22H24N3O3Na79Br: 480.0899. Found: 480.0891 [(M+Na)+].
- The compound (Yd) (190 mg, 0.459 mmol) was obtained from indolic N-hydroxylamine (Xd) (290 mg, 0.70 mmol) and MnO2 (305 mg, 3.50 mmol) as a beige foam. Yield: 66%.
- IR (neat): 3265, 2980, 1695, 1505, 1450, 1365, 1250, 1160, 1130, 895, 795, 750, 690 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 9H), 3.71-3.76 (m, 1H), 3.95-4.03 (m, 1H), 5.39-5.55 (m, 2H), 6.90-6.98 (m, 2H), 7.02-7.10 (m, 1H), 7.30-7.39 (m, 3H), 7.59-7.62 (m, 2H), 8.20-8.24 (m, 2H), 9.70 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.2 (3C), 42.7, 71.5, 79.8, 108.9, 112.7, 117.8, 122.4, 125.6, 125.7, 126.9, 128.5 (2 C), 128.9 (2 C), 129.9, 130.8, 134.4, 135.3, 156.2 ppm. LRMS (ESI): m/z (%) = 436 (40) [(M+Na)+], 414 (34) [(M+H)+], 293 (12), 237 (100), 193 (12).
- The compound (Ye) (205 mg, 0.496 mmol) was obtained from indolic N-hydroxylamine (Xe) (290 mg, 0.70 mmol) and MnO2 (305 mg, 3.50 mmol) as a beige foam. Yield: 71%.
- IR (neat): 3275, 2970, 1685, 1505, 1450, 1365, 1250, 1160, 1130, 905, 800, 750, 690 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 9H), 3.67-3.80 (m, 1H), 3.94-4.06 (m, 1H), 5.43-5.58 (m, 2H), 6.93-7.07 (m, 3H), 7.33-7.38 (m, 3H), 7.48-7.53 (m, 1H), 7.61 (s, 1H), 8.20-8.24 (m, 2H), 9.65 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.2 (3C), 42.6, 71.7, 79.8, 109.3, 111.6, 119.2, 120.5, 124.4, 124.9, 127.9, 128.5 (2 C), 128.9 (2 C), 129.9, 130.8, 135.4, 136.4, 156.3 ppm. LRMS (ESI): m/z (%) = 436 (81) [(M+Na)+], 414 (33) [(M+H)+], 293 (16), 237 (100), 193 (14).
- Compound (Yf) (210 mg, 0.529 mmol) was obtained from N-hydroxylamine (Xf) (320 mg, 0.80 mmol) and MnO2 (348 mg, 4.00 mmol) as a beige foam. Yield: 66%.
- IR (neat): 3465, 3295, 3060, 2970, 1685, 1505, 1455, 1370, 1240, 1175, 1150, 1130, 940, 785, 695, 670 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 3.78-3.87 (m, 1H), 3.98-4.07 (m, 1H), 5.22-5.29 (m, 1H), 5.52-5.57 (m, 1H), 6.88 (dt, J = 2.5 and 9.1 Hz, 1H), 7.18 (dd, J = 4.4 and 9.0 Hz, 1H), 7.34-7.42 (m, 5H), 8.22-8.25 (m, 2H), 8.86 (br s, 1H, NH). 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 27.9 (3C), 42.2, 71.4, 79.6, 103.0 (d, J = 23.1 Hz), 110.2 (d, J = 26.3 Hz), 112.1 (d, J = 9.6 Hz), 125.7, 128.2 (2 C), 128.9 (2 C), 129.6, 130.8, 132.4, 136.2, 156.7, 157.7 (d, J = 234.7 Hz). 19F NMR (282 MHz, CDCl3): δ = -123.3 (dt, J = 4.3 and 9.3 Hz, 1F) ppm. LRMS (ESI): m/z (%) = 420 (47) [(M+Na)+], 398 (28) [(M+H)+], 277 (15), 221 (100), 177 (15).
- Compound (Yg) (200 mg, 0.504 mmol) was obtained from indolic N-hydroxylamine (Xg) (280 mg, 0.70 mmol) and MnO2 (305 mg, 3.50 mmol) as a beige foam. Yield: 72%.
- IR (neat): 3370, 3160, 2985, 2910, 1685, 1530, 1455, 1320, 1270, 1135, 950, 835, 685, 675 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 3.80-3.88 (m, 1H), 3.98-4.07 (m, 1H), 5.22-5.29 (m, 1H), 5.56-5.60 (m, 1H), 6.87 (dt, J = 2.3 and 9.4 Hz, 1H), 6.95 (dd, J = 2.1 and 9.4 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.39-7.42 (m, 3H), 7.57 (s, 1H), 7.62-7.67 (m, 1H), 8.21-8.25 (m, 2H), 8.80 (br s, 1H, NH). 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 27.6 (3C), 42.0, 71.4, 79.3, 97.3 (d, J = 23.8 Hz), 108.0 (d, J = 25.0 Hz), 108.7, 118.7 (d, J = 8.7 Hz), 122.3, 124.2 (d, J = 3.4 Hz), 128.1 (2 C), 128.9 (2 C), 129.5, 130.6, 135.9 (d, J = 12.6 Hz), 136.4, 156.6, 159.5 (d, J = 237.2 Hz). 19F NMR (282 MHz, CDCl3): δ = -120.4 (m, 1F) ppm. LRMS (ESI): m/z (%) = 420 (100) [(M+Na)+], 398 (12) ([M+H)+], 331 (8), 277 (6), 221 (36), 177 (5).
- Compound (Yh) (240 mg, 0.475 mmol) was obtained from indolic N-hydroxylamine (Xh) (355 mg, 0.70 mmol) and MnO2 (305 mg, 3.50 mmol) as a beige foam. Yield: 68%.
- IR (neat): 3275, 2970, 2930, 1695, 1505, 1450, 1365, 1250, 1160, 880, 795, 750, 690 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9H), 3.71-3.81 (m, 1H), 3.94-4.05 (m, 1H), 5.29-5.40 (m, 1H), 5.48-5.55 (m, 1H), 6.87 (d, J = 9.5 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 1.4 and 8.6 Hz, 1H), 7.36-7.41 (m, 3H), 7.61 (s, 1H), 7.97 (s, 1H), 8.21-8.25 (m, 2H), 9.50 (br.s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.8, 71.3, 80.0, 83.7, 108.7, 113.6, 125.1, 127.1, 128.4, 128.6 (2 C), 128.9 (2 C), 130.0, 130.6, 130.8, 135.1, 135.3, 156.2 ppm. LRMS (ESI): m/z (%) = 528 (100) [(M+Na)+], 506 (40) [(M+H)+], 439 (6), 329 (86).
- The compound (Yi) can be obtained from indolic N-hydroxylamine (Xi) according to the procedure described in this patent.
- The compounds (Yj), (Yk) and (Yl) can be obtained from indolic N-hydroxylamines (Xj), (Xk) and (XI) respectively according to the procedure described in this patent.
- To a stirred solution of one equivalent of indolic nitrone (Ya-l) in methanol, three equivalents of hydroxylamine hydrochloride were added. The resulting mixture was stirred during 1 hour at room temperature and then the solution was concentrated under vacuum. A saturated aqueous solution of NaHCO3 was added. The mixture was then extracted with diethyl ether (3x10 mL) and the collected organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude mixture was purified by column chromatography using EtOAc-pentane (10/90 - 99/1) to afford the corresponding pure product (Za-l).
- Compound (Za) (265 mg, 0.91 mmol) was obtained from indolic nitrone (Ya) (531 mg, 1.40 mmol) and NH2OH.HCl (292 mg, 4.20 mmol) as a beige foam. Yield: 65%.
- 1H NMR (300 MHz, CDCl3): δ□= 1.43 (s, 9H, C(CH3)3), 3.4-3.6 (m, 1H, H of CH2), 3.6-3.8 (m, 1H, H of CH2), 4.37 (t, J = 5.2 Hz, 1H, CHN), 5.04 (br s, 1H, NHBoc), 7.00 (s, 1H, H indol), 7.09 (t , J = 7.0 Hz, 1H, H indol), 7.15 (t, J = 7.0 Hz, 1H, H indol), 7.29 (d, J = 7.9 Hz, 1H, H indol), 7.58 (d, J = 7.9 Hz, 1H, H indol), 8.66 (s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3,): δ = 28.4 (C(CH3)3), 42.5 (CH2N), 58.5 (CHN), 79.7 (C(CH3)3), 111.4 (CH indol), 112.5 (C indol), 118.9 (CH indol), 119.6 (CH indol), 122.2 (CH indol), 122.8 (CH indol), 126.2 (C indol), 136.0 (C indol), 157.0 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z= 314 □(M+Na)+□, 292 [(M+H)+], 279, 203. HRMS: (ESI) calcd for C15H22N3O3 [(M+H)+]: 292.1661. Found: 292.1661.
- Compound (Zb) (145 mg, 0.39 mmol) was obtained from nitrone (Yb) (320 mg, 0.70 mmol) and NH2OH.HCl (146 mg, 2.10 mmol) as a beige foam. Yield : 56%.
- Mp: 87 °C. IR (KBr): 3419, 3307, 2977, 2936, 1692, 1516, 1456, 1366, 1254, 1172, 805 cm-1. 1H NMR (300 MHz, CDCl3,): δ = 1.43 (s, 9H, (CH3)3C), 3.35-3.65 (m, 2H, CH2N), 4.25 (t, J = 5.4 Hz, 1H, CHN), 5.11 (br s, 1H, NHBoc), 6.98 (d, J = 1.7 Hz, 1H, H indol), 7.12 (d, J = 8.7 Hz, 1H, H indol), 7.19 (dd, J = 1.7 and 8.7 Hz, 1H, H indol), 7.72 (s, 1H, H indol), 9.05 (s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 ((CH3)3C), 42.5 (CH2N), 58.6 (CHN), 79.9 ((CH3)3 C), 112.4 (C indol), 112.8 (C indol), 112.9 (CH indol), 121.7 (CH indol), 124.0 (CH indol), 124.9 (CH indol), 128.0 (C indol), 134.7 (C indol), 157.1 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 370 and 372 [(M+H)+], 298 and 300, 281 and 283. HRMS (ESI) calcd for C15H20N3O3 79BrNa [(M+Na)+]: 392.0586. Found: 392.0591.
- Compound (Zc) (170 mg, 0.46 mmol) was obtained from nitrone (Yc) (366 mg, 0.80 mmol) and NH2OH.HCl (167 mg, 2.40 mmol) as a beige foam. Yield : 57%.
- Mp: 80 °C. IR (KBr): 3419, 3302, 2979, 2934, 1693, 1518, 1454, 1369, 1253, 911, 807, 736 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H, C(CH3)3), 3.35-3.55 (m, 1H, H of CH2N), 3.55-3.75 (m, 1H, H of CH2N), 4.35 (t, J = 5.1 Hz, 1H, CHN), 4.96 (br s, 1H, NHBoc), 7.06 (s, 1H, OH), 7.17 (dd, J = 1.4 and 8.6 Hz, 1H, H indol), 7.46 (s, 1H, H indol), 7.47 (d, J = 7.4 Hz, 1H, H indol), 8.66 (br s, 1H, NH indol) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (C(CH3)3), 42.4 (CH2N), 58.5 (CHN), 80.0 (C(CH3)3), 112.9 (C indol), 114.4 (CH indol), 115.7 (C indol), 120.3 (CH indol), 123.0 (CH indol), 123.4 (CH indol), 125.2 (C indol), 136.9 (C indol), 157.1 (C=O) ppm. LRMS (ESI): m/z = 370 and 372 [(M+H)+], 281 and 283. HRMS (ESI) calcd for C15H21N3O3 79Br [(M+H)+]: 370.0766. Found: 370.0768 and 372.0747.
- Compound (Zd) (80 mg,0.246 mmol) was obtained from indolic nitrone (Yd) (165 mg, 0.40 mmol) and NH2OH.HCl (83 mg, 1.20 mmol) as a beige foam. Yield : 62%.
- IR (neat): 3410, 3290, 2975, 2925, 1685, 1515, 1455, 1365, 1250, 1160, 895, 860, 795 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 3.40-3.45 (m, 1H), 3.56-3.70 (m, 1H), 4.29 (t, J = 5.3 Hz, 1H), 5.03 (br s, 1H), 7.05-7.10 (m, 2H), 7.20 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 8.84 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.5, 58.7, 79.9, 112.4, 118.7, 122.5, 124.1, 125.3, 127.3, 134.5 (2 C), 157.1 ppm. LRMS (ESI): m/z (%) = 348 (14) [(M+Na)+], 326 (16) [(M+H)+], 237 (100), 193 (12).
- Compound (Ze) (100 mg, 0.308 mmol) was obtained from nitrone (Ye) (165 mg, 0.40 mmol) and NH2OH.HCl (83 mg, 1.20 mmol) as a beige foam. Yield: 77%.
- IR (neat): 3415, 3280, 2975, 2925, 1685, 1510, 1455, 1365, 1250, 1160, 905, 800 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H), 3.40-3.62 (m, 2H), 4.30 (t, J = 5.4 Hz, 1H), 5.06 (br s, 1H), 6.98-7.03 (m, 2H), 7.24-7.26 (m, 1H), 7.45 (d, J = 9.0 Hz, 1H), 8.87 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.4, 58.5, 79.9, 111.3, 119.8, 120.3, 123.3, 124.8, 128.0, 136.4 (2 C), 157.1 ppm. LRMS (ESI): m/z (%) = 348 (18) [(M+Na)+], 326 (14) [(M + H)+], 301 (12), 237 (100), 193 (11).
- Compound (Zf) (80 mg, 0.259 mmol) was obtained from indolic nitrone (Yf) (179 mg, 0.45 mmol) and NH2OH.HCl (94 mg, 1.35 mmol) as a beige foam. Yield: 58%.
- IR (neat): 3415, 3300, 2975, 2925, 1685, 1510, 1490, 1455, 1365, 1250, 1160, 935, 850, 795 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9H), 3.43-3.50 (m, 1H), 3.55-3.68 (m, 1H), 4.28 (t, J = 5.3 Hz, 1H), 5.04 (br s, 1H), 6.88 (dt, J = 2.4 and 9.0 Hz, 1H), 7.07 (s, 1H), 7.19 (dd, J = 4.4 and 8.8 Hz, 1H), 7.21-7.30 (m, 1H), 8.79 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.4, 58.7, 79.9, 104.1 (d, J = 23 .2 Hz), 110.6 (d, J = 26.5 Hz), 112.0 (d, J = 9.2 Hz), 124.4, 126.6 (d, J = 10.2 Hz), 132.6 (2 C), 157.2, 157.8 (d, J = 236.7 Hz) ppm. 19F NMR (282 MHz, CDCl3): δ = -124.1 (m, 1F) ppm. LRMS (ESI): m/z (%) = 332 (49) [(M+Na)+], 310 (7) [(M+H)+], 239 (44), 221 (100).
- Compound (Zg) (50 mg, 0.162 mmol) was obtained from indolic nitrone (Yg) (159 mg, 0.40 mmol) and NH2OH.HCl (83 mg, 1.20 mmol) as a beige foam. Yield: 40%.
- IR (neat): 3415, 3290, 2975, 2920, 1685, 1500, 1455, 1365, 1250, 1160, 1140, 950, 800 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H), 3.45-3.51 (m, 1H), 3.60-3.65 (m, 1H), 4.34 (t, J = 5.3 Hz, 1H), 5.02 (br s, 1H), 6.83 (dt, J = 2.3 and 9.6 Hz, 1H), 6.97 (dd, J = 2.3 and 9.6 Hz, 1H), 7.03 (s, H), 7.49 (dd, J = 5.3 and 8.7 Hz, 1H), 8.74 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (3C), 42.4, 58.6, 79.9, 97.6 (d, J = 26.2 Hz), 108.4 (d, J = 24.5 Hz), 122.8, 122.9, 128.8 (d, J = 12.2 Hz), 136.0, 136.1, 158.4, 160.0 (d, J = 238.5 Hz) ppm. 19F NMR (282 MHz, CDCl3): δ = -120.7 (m, 1F) ppm. LRMS (ESI): m/z (%) = 332 (43) [(M+Na)+], 310 (6) [(M+H)+], 239 (100), 221 (75).
- Compound (Zh) (125 mg, 0.30 mmol) was obtained from nitrone (Yh) (202 mg, 0.40 mmol) and NH2OH.HCl (83 mg, 1.20 mmol) as a beige foam. Yield: 75%.
- IR (neat): 3410, 3280, 2975, 2925, 1685, 1510, 1455, 1365, 1250, 1160, 795, 750 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H), 3.40-3.49 (m, 1H), 3.50-3.61 (m, 1H), 4.26 (t, J = 5.2 Hz, 1H), 5.08 (br s, 1H), 6.95 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 1.4 and 8.5 Hz, 1H), 7.94 (s, 1H), 8.96 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.5, 58.5, 79.9, 83.0, 112.1, 113.4, 123.5, 127.9, 128.8, 130.3, 135.1, 157.0 ppm. LRMS (ESI): m/z (%) = 440 (18) [(M+Na)+], 418 (56) [(M + H)+], 376 (100).
- The compound (Zi) can be obtained from indolic N-hydroxylamine (Yi) according to the procedure described in this patent.
- Compound (Zj) (75 mg, 0.202 mmol) was obtained from nitrone (Yj) (137 mg, 0.30 mmol) and NH2OH.HCl (63 mg, 0.90 mmol) as a beige foam. Yield: 68%.
- IR (neat): 3415, 3275, 2975, 2925, 1685, 1510, 1365, 1335, 1250, 1160, 775, 735 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9H), 3.57-3.75 (m, 2H), 5.06-5.16 (m, 2H), 6.93 (t, J = 7.8 Hz, 1H), 7.18-7.25 (m, 3H), 9.18 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.3 (3C), 42.2, 57.2, 79.8 (C), 110.9, 112.9, 113.3, 122.8, 124.2, 124.4, 124.5, 137.5, 157.4 ppm. LRMS (ESI): m/z (%) = 384 (28) [(M+Na)+], 372 (14) [(M+H)+], 360 (11), 328 (100), 293 (23).
- The compounds (Zk) and (Zl) can be obtained from indolic N-hydroxylamines (Yk) and (Yl) respectively according to the procedure described in this patent.
- To a stirred solution of primary hydroxylamine (Za) (70 mg (0.24 mmol) in 1 mL of methanol was added 0.51 mL of a 15% aqueous solution of titanium trichloride (74 mg, 0.48 mmol). The resulting mixture was stirred at room temperature during 30 min. A large excess of an aqueous 20% solution of sodium hydroxide saturated with sodium chloride was added. Methanol was removed under vacuum and the crude mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (Eluent: EtOAc). The product (1a) was obtained as a white solid (64 mg, 0.23 mmol). Yield: 97%.
- For this procedure, see: Xavier Guinchard, "thèse de l'Université Joseph Fourier, Grenoble 1", 2006.
- To a stirred solution of indolic N-hydroxylamine (Xa) (2.0 g, 5.25 mmol) in 93 mL of methanol and 3.5 mL of acetic acid was added 0.8 g of Pearlman's catalyst (Pd(OH)2). Argon was replaced by hydrogen. The resulting mixture was then stirred at room temperature during 40h. It was then filtered through celite. The resulting filtrate was treated by a 6N aqueous solution of sodium hydroxide. Methanol was then evaporated under vacuum. The resulting aqueous phase was extracted three times with EtOAc. Combined organics layers were washed with brine and dried over anhydrous MgSO4. After the removal of the solvent, the residue was purified by column chromatography on silica gel (Eluent: EtOAc). The product (Za) was obtained as a white solid (1.31 g, 4.75 mmol). Yield: 90%.
- Mp: 145-146 °C. IR (neat): 3404, 3339, 3308, 3053, 2977, 2930, 1703, 1693, 1682, 1537, 1531, 1519, 1514, 1504, 1455, 1393, 1367, 1337, 1251, 1170 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 9H, C(CH3)3), 1.76 (br s, 2H, NH2), 3.39 (ddd, J = 6.5, 7.0 and 13.0 Hz, 1H, 1H of CH2N), 3.57 (ddd, J = 5.5, 6.5 and 13.0 Hz, 1H, 1H of CH2N), 4.41 (dd, J = 5.5 and 7.0 Hz, 1H, CHN), 4.90 (br s, 1H, NHBoc), 7.12 (ddd, J = 1.0, 7.5 and 7.5 Hz, 1H, H indol), 7.13 (s, 1H, H indol), 7.20 (ddd, J = 1.0, 7.5 and 7.5 Hz, 1H, H indol), 7.37 (d, J = 8.0 Hz, 1H, H indol), 7.71 (d, J = 8.0 Hz, 1H, H indol), 8.30 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (C(CH3)3), 47.5 (CH2), 48.7 (CHN), 79.3 (C(CH3)3), 111.3 (CH indol), 118.6 (C indol), 119.3 (CH indol), 119.6 (CH indol), 121.0 (CH indol), 122.3 (CH indol), 125.9 (C indol), 136.6 (C indol), 156.2 (C=O) ppm. LRMS (DCI, NH3+isobutane): m/z = 276 [(M+H)+]. Anal. calcd for C15H21N3O2 : C, 65.43; H, 7.69; N, 15.26. Found: C, 65.22; H, 7.69; N, 15.19.
- To a stirred solution of primary hydroxylamine (Zb) (556 mg, 1.50 mmol) in 5 mL of methanol was added 3.53 mL of a 15% aqueous solution of titanium trichloride (509 mg, 3.3 mmol). The resulting mixture was stirred at room temperature during 30 min. A large excess of a 20% aqueous solution of sodium hydroxide saturated with sodium chloride was added. Methanol was removed under vacuum and the crude mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried on anhydrous MgSO4 and evaporated. The obtained residue was purified by column chromatography on silica gel (Eluent: EtOAc). The product (Zb) was obtained as a white solid (438 mg, 1.24 mmol). Yield: 83%. Mp: 151 °C. IR (film): 3423, 3296, 2977, 2925, 1692, 1508, 1456, 1363, 1280, 1250, 1164 cm-1 . 1H NMR (300 MHz, MeOD): δ = 1.41 (s, 9H, C(CH3)3), 3.20-3.50 (m, 2H, CH2N), 4.28 (dd, J = 5.9 and 7.3 Hz, 1H, CHN), 7.18 (dd, J = 1.8 and 8.6 Hz, 1H, H indol), 7.26 (d, J = 8.5 Hz, 1H, H indol), 7.26 (s, 1H, H indol), 7.81 (d, J = 1.5 Hz, 1H, H indol) ppm. 13C NMR (75.5 MHz, MeOD): δ = 28.7 (C(CH3)3), 48.9 (CH2), 49.4 (CHN), 80.1 (C(CH3)3), 113.1 (C indol), 114.0 (CH indol), 117.6 (C indol), 122.3 (CH indol), 124.2 (CH indol), 125.3 (CH indol), 129.2 (C indol), 136.7 (C indol), 158.5 (C=O) ppm. LRMS (ESI): m/z = 354 and 356 [(M+H)+]. HRMS (ESI) calcd for C15H21N3O2 79 Br: 354.0817. Found: 354.0837 [(M+H)+].
- To a stirred solution of 280 mg (0.756 mmol) of primary hydroxylamine (Zc) in 3 mL of methanol was added 1.78 mL of a 15% aqueous solution of titanium trichloride (257 mg, 1.66 mmol). The resulting mixture was stirred at room temperature during 30 min. A large excess of a 20% aqueous solution of sodium hydroxide saturated with sodium chloride was added. Methanol was removed under vacuum and the crude mixture was extracted three times by EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous MgSO4 and evaporated. The resulting residue was purified by column chromatography on silica gel (Eluent: EtOAc) to afford the product (1c) as a white solid (248 mg, 0.70 mmol). Yield: 92%.
- Mp: 80 °C. IR (neat): 3287, 2977, 2931, 1692, 1505, 1458, 1364, 1171, 803 cm-1. 1H NMR (300 MHz, MeOD): δ = 1.42 (s, 9H, C(CH3)3, 3.20-3.30 (m, 1H, CH of CH2), 3.42-3.50 (m, 1H, H of CH2), 4.31 (dd, J = 5.5 and 7.9 Hz, 1H, CHN), 7.13 (dd, J = 1.8 and 8.5 Hz, 1H, H indol), 7.24 (s, 1H, H indol), 7.51 (d, J = 1.7 Hz, 1H, H indol), 7.58 (d, J = 8.2 Hz, 1H, H indol) ppm. 13C NMR (75.5 MHz, MeOD): δ = 28.7 (C(CH3)3), 48.8 (CH2), 49.6 (CHN), 80.2 (C(CH3)3), 115.2 (CH indol), 114.0 (C indol), 118.0 (C indol), 121.1 (CH indol), 123.0 (CH indol), 123.6 (CH indol), 126.4 (C indol), 139.0 (C indol), 158.5 (C=O) ppm. LRMS (ESI): m/z= 354 and 356 [(M+H)+]. HRMS (ESI) calcd for C15H21N3O2 79 Br: 354.0817. Found: 354.0812 [(M+H)+].
- To a stirred solution of indolic N-hydroxylamine (Zd) (326 mg, 1.0 mmol) in 5 mL of methanol was added 1.7 mL of 15% aqueous solution of titanium trichloride (339 mg, 2.2 mmol). The resulting mixture was stirred at room temperature during 30 min. A large excess of a 20% aqueous solution of sodium hydroxide saturated with NaCl was added. Methanol was then removed under vacuum and the crude mixture was extracted with EtOAc (3x20 mL). Combined organic layers were washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Pure amine (1c) was obtained as a white solid (288 mg, 0.932 mmol). Yield: 93%.
- 1H NMR (300 MHz, CD3OD): δ = 1.41 (s, 9H), 3.39-3.45 (m, 2H), 4.30-4.34 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.28-7.33 (m, 2H), 7.66 (s, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.8 (3C), 48.7, 49.3, 80.2, 113.6, 117.2, 119.2, 122.8, 124.5, 125.7, 128.6, 136.5, 156.5 ppm. LRMS (ESI): m/z (%) = 310 (13) [(M+H)+], 237 (100) [(M - C4H9O+H)+].
- These compounds can be prepared according the method described in this patent.
- tert-Butyl 2-amino-2-(6-chloro-1H-indol-3-yl)ethylcarbamate (1e)
- tert-Butyl 2-amino-2-(5-fluoro-1H-indol-3-yl)ethylcarbamate (1f)
- tert-Butyl 2-amino-2-(6-fluoro-1H-indol-3-yl)ethylcarbamate (1g)
- tert-Butyl 2-amino-2-(5-iodo-1H-indol-3-yl)ethylcarbamate (1h)
- tert-Butyl 2-amino-2-(6-iodo-1H-indol-3-yl)ethylcarbamate (1i)
- tert-Butyl 2-amino-2-(4-bromo-1H-indol-3-yl)ethylcarbamate (1j)
- tert-Butyl 2-amino-2-(7-bromo-1H-indol-3-yl)ethylcarbamate (1k)
- tert-Butyl 2-amino-2-(2-bromo-1H-indol-3-yl)ethylcarbamate (1l)
- The compounds 2-4 were prepared from the corresponding 2-(1H-indol-3-yl)-2-oxoacetyl chlorides (8a-c) and indolic primary amines (1a) and (1b) according the procedure described in the literature : X. Guinchard, Y. Vallée, J.-N. Denis, « Total syntheses of brominated marine sponge alkaloids », Org. Lett. 2007, 9, 3761-3764.
- To a cooled solution of amine (1a) (200 mg, 0.73 mmol) at 0 °C in THF was added Et3N (73 mg, 0.73 mmol) and then the acid chloride (8a) (150 mg, 0.73 mmol). Reaction was stirred at 0 °C during two hours and then H2O was added. The resulting mixture was extracted twice with EtOAc. Combined organic layers were washed with brine and dried over anhydrousMgSO4. After the removal of the solvents, the amide 2 was obtained as a yellow solid (317 mg, 0.71 mmol). Yield: 97%.
- 1H NMR (300 MHz, (CD3)2CO): δ = 1.39 (s, 9H, C(CH 3)3), 3.65-3.85 (m, 2H, CH2), 5.60 (m, 1H, CHN), 6.28 (br s, 1H, NHBoc), 7.05 (dt, J= 1.0 and 6.9 Hz, 1H, H indol), 7.12 (dt, J= 1.3 and 7.0 Hz, 1H, H indol), 7.20-7.30 (m, 2H, H indol), 7.41 (d, J= 8.0 Hz, 1H, H indol), 7.44 (d, J= 2.2 Hz, 1H, H indol), 7.52-7.60 (m, 1H, H indol), 7.79 (d, J= 7.9 Hz, 1H, H indol), 8.15-8.28 (m, 1H, NH), 8.30-8.40 (m, 1H, H indol), 9.05-9.1 (m, 1H, H indol), 10.20 (br s, 1H, NH) 11.22 (br s, 1H, NH). 13C NMR (75.5 MHz, DMSO-d6): δ = 28.2 (C(CH 3)3), 45.0 (CH2), 45.9 (CHN), 77.8 (C(CH3)3), 111.5 (CH indol), 112.2 (C indol), 112.5 (CH indol), 113.7 (C indol), 118.6 (C indol), 121.1 (CH indol), 121.2 (CH indol), 122.5 (CH indol), 122.7 (CH indol), 123.4 (CH indol), 126.2 (C indol), 136.1 (C indol), 136.2 (C indol), 138.3 (CH indol), 156.0 (C indol), 162.9 (C=O), 163.0 (C=O), 182.1 (C=O) ppm. LRMS (ESI): m/z = 469 [(M+Na)+], 485 [(M+K)+], 915 [(2M+Na)+]. HRMS (ESI) calcd for C25H26N4OK [(M+K)+]: 485.1591. Found: 485.1586.
- In a dry flask under argon, the indolic primary amine (1a) (80 mg, 0.29 mmol) and triethylamine (47 mg, 0.465 mmol) were dissolved in 3 mL of dry dichloromethane and 0.1 mL of dry THF. After cooling this solution to 0 °C, the acid chloride (8c) (100 mg, 0.349 mmol) was added and the mixture was stirred at 0 °C for 20 minutes. The reaction was then quenched with an aqueous saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 7/3) to afford the desired product 3 (120 mg, 0.23 mmol) as a white solid. Yield: 79 %.
- Mp: 145 °C. IR (ATR): 3310, 2976, 1682, 1621, 1495, 1437, 1410, 1244, 1158 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 1.36 (s, 9H, CH3), 3.48-3.57 (m, 2H, CH2), 5.42-5.49 (m, 1H, CH), 6.98-7.11 (m, 3H, CH and NH), 7.34-7.41 (m, 3H, CH), 7.68 (d, J = 7.8 Hz, 1H, CH), 7.74 (s, 1H, CH), 8.16 (d, J = 8.7 Hz, 1H, CH), 8.77-8.80 (m, 2H, CH and NH), 10.98 (br s, 1H, NH), 12.30 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 28.0 (CH3), 43.9 (CH2), 45.9 (CH), 77.7 (C), 111.4 (CH), 112.12 (C), 113.6 (C), 115.2 (CH), 115.8 (C), 118.52 (CH), 118.54 (CH), 121.1 (CH), 122.7 (CH), 122.8 (CH), 125.2 (C), 125.3 (CH), 126.1 (CH), 136.1 (C), 137.1 (C), 139.1 (CH), 155.9 (C), 162.6 (C), 182.2 (C) ppm.
- In a dry flask under argon, the indolic primary amine (1a) (170 mg, 0.48 mmol) and triethylamine (77 mg, 0.768 mmol) were dissolved in 5 mL of dry dichloromethane and 1 mL of dry THF. After cooling this solution to 0 °C, the acid chloride (8b) (165 mg, 0.576 mmol) was added and the mixture was stirred at 0 °C for one hour. The reaction was then quenched with an aqueous saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 7/3) to afford the desired product 4 (180 mg, 0.30 mmol) as a white solid. Yield: 62 %.
- Mp : 207 °C. IR (ATR): 3480, 3332, 3175, 1672, 1615, 1494, 1425, 1286, 1226, 1149 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 1.34 (s, 9H, CH3), 3.45-3.52 (m, 2H, CH2), 5.34-5.40 (m, 1H, CH), 6.98 (t, J = 5.6 Hz, 1H, NH), 7.19 (d, J = 8.4 Hz, 1H, CH), 7.31 (d, J = 8.8 Hz, 1H, CH), 7.38-7.42 (m, 2H, CH), 7.51 (d, J = 8.4 Hz, 1H, CH), 7.84 (s, 1H, CH), 8.34 (d, J = 1.6 Hz, 1H, CH), 8.74 (s, 1H, CH), 8.92 (d, J = 8.8 Hz, 1H, NH), 11.19 (br s, 1H, NH), 12.39 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 28.1 (CH3), 43.8 (CH2), 45.6 (CH), 77.7 (C), 111.23 (C), 111.6 (C), 113.4 (CH), 113.6 (C), 114.6 (CH), 115.2 (C), 120.9 (CH), 123.2 (CH), 123.5 (CH), 124.5 (CH), 125.9 (CH), 127.9 (C), 128.0 (C), 134.7 (C), 135.0 (C), 139.2 (CH), 155.8 (C), 162.7 (C), 182. (C) ppm.
- The synthesis of this compound was described in the literature. See: J.-N. Denis, H. Mauger, Y. Vallée Tetrahedron Lett. 1997, 38, 8515-8518; H. Chalaye-Mauger, J.-N. Denis, M.-T. Averbuch-Pouchot, Y. Vallée Tetrahedron 2000, 56, 791-804. It was prepared according to the procedure described in these references.
- In a dry flask, freshly distilled acetaldehyde (1.39 g, 31.5 mmol) was dissolved in dry dichloromethane (50 mL). To this solution, N-benzylhydroxylamine (3.70 g, 30 mmol) and excess of anhydrous MgSO4 (15 g) were added. The mixture was stirred for 1 hour at room temperature under argon. The solution was then filtered through a short pad of celite to remove MgSO4 and concentrated under vacuum. The desired product (ba) was obtained without any further purification as a white solid. Yield: 100%.
- 1H NMR (300 MHz, DMSO-d6): δ = 1.82 (d, J = 5.7 Hz, 3H, CH3), 4.87 (s, 2H, CH2), 7.21 (q, J = 5.7 Hz, 1H, CH), 7.29-7.43 (m, 5H, CH) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 12.2 (CH3), 67.7 (CH2), 127.8 (CH), 128.2 (CH), 128.8 (CH), 133.0 (CH), 134.5 (C) ppm. LRMS (ESI): m/z = 150 [(M+H)+].
- The synthesis of this compound was described in the litterature. See: J.-N. Denis, H. Mauger, Y. Vallée Tetrahedron Lett. 1997, 38, 8515-8518 ; H. Chalaye-Mauger, J.-N. Denis, M.-T. Averbuch-Pouchot, Y. Vallée Tetrahedron 2000, 56, 791-804. It was prepared according to the procedure described in these references.
- In a dry flask cooled at 0 °C under argon, freshly distilled acetyl chloride (2.85 mL, 40 mmol) was slowly added to dry methanol (40 mL). This solution was stirred for 10 minutes at 0 °C in order to obtain a HCl solution in methanol. In another dry flask, 5-bromoindole (ab) (3.92 g, 20 mmol) and nitrone (ba) (3.07 g, 20.6 mmol) were dissolved n dry methanol (50 mL) and this solution was slowly (over 5 minutes) added to the previous one. Temperature was maintained around 0 °C. The reaction was stirred for 2h30 at 0 °C and for 45 minutes at room temperature before quenching with a saturated aqueous solution of NaHCO3. Methanol was then removed by evaporation under reduced pressure. The crude material was extracted three times with dichloromethane, washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated. After purification by flash chromatography (AcOEt/pentane, 2/8 then 1/1), the desired product (cb) was obtained as a white solid. Yield: 59%.
- 1H NMR (300 MHz, DMSO-d6): δ = 1.49 (d, J = 6.6 Hz, 3H, CH3), 3.47-3.64 (m, 2H, CH2), 4.11-4.16 (m, 1H, CH), 7.15-7.33 (m, 8H, CH), 7.67 (s, 1H, OH), 7.95 (s, 1H, CH), 11.11 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 18.0 (CH3), 59.1 (CH), 59.6 (CH2), 110.8 (C), 113.2 (CH), 122.4 (CH), 123.2 (CH), 124.7 (CH), 126.2 (CH), 127.6 (CH), 128.3 (C), 128.7 (CH), 135.0 (C), 139.7 (C) ppm. LMRS (ESI): m/z = 343 and 345 [(M-H)-].
- The synthesis of this compound is described in the following paper: O. N. Burchak, E. Le Pihive, L. Maigre, X. Guinchard, P. Bouhours, C. Jolivalt, D. Schneider, M. Maurin, C. Giglione, T. Meinnel, J.-M. Paris, J.-N. Denis, « Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents », Bioorg. Med. Chem. 2011, 19, 3204-3215. It's structure was protected by the following patent : J.-N. Denis, X. Guinchard, N. Moreau, L. Neuville, Y. Vallée. « Synthesis of new indole derivatives, their preparation processes, and their antibacterial uses »,
WO 2008110690 A2 20080918 - Compound (cb) (3.54g, 10.27 mmol) was dissolved in warm toluene (90 mL). After complete dissolution, MnO2 (4.47 g, 51.37 mmol) was added. The solution was refluxed for 10 minutes and filtered through a short pad of celite. The celite was carefully washed with ethyl acetate. Then, the clear brown solution was concentrated to afford thick brown oil. This crude material was purified by flash chromatography with silica pre-treated with 2.5% of triethylamine (neat Et2O then Et2O with 1% and 2% of methanol) and the desired product (eb) was obtained as a yellowish solid. Yield: 47%.
- 1H NMR (400 MHz, DMSO-d6): δ = 1.80 (d, J = 6.8 Hz, 3H, CH3), 5.66 (q, J = 6.8 Hz, 1H, CH), 7.19 (dd, J = 2.0 and 8.8 Hz, 1H, CH), 7.34-7.42 (m, 4H), 7.59 (d, J = 2.4 Hz, 1H, CH), 7.95 (d, J = 2.0 Hz, 1H, CH), 8.15 (s, 1H, CH), 8.22 (dd, J = 2.4 and 8.0 Hz, J = 2.4 Hz, 2H, CH), 11.39 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 19.8 (CH3), 68.1 (CH), 112.6 (C), 113.8 (C), 114.6 (CH), 115.1 (CH), 122.2 (CH), 124.3 (CH), 124.7 (CH), 127.4 (CH), 128.7 (C), 128.8 (CH), 129.2 (CH), 130.5 (CH), 131.9 (CH), 132.1 (C), 135.8 (C) ppm. LRMS (ESI): m/z = 341 and 343 [(M-H)-].
- The synthesis of this compound is described in the following paper: O. N. Burchak, E. Le Pihive, L. Maigre, X. Guinchard, P. Bouhours, C. Jolivalt, D. Schneider, M. Maurin, C. Giglione, T. Meinnel, J.-M. Paris, J.-N. Denis, « Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents », Bioorg. Med. Chem. 2011, 19, 3204-3215. It was prepared according to the general procedure used for the synthesis of indolic N-hydroxylamines (Z).
- Under argon, compound (eb) (1.57 g, 4.57 mmol) was stirred for 3 hours at room temperature with hydroxylamine hydrochloride (1.59 g, 22.88 mmol) in methanol (15 mL). The solution was then concentrated, dissolved in ethyl acetate, washed with a saturated aqueous solution of NaHCO3 and brine. After drying over anhydrous MgSO4, the organic layer was evaporated. The residue was purified by flash chromatography (AcOEt/pent ane, from 1/1 to neat EtOAc) to afford the desired product (fb) as a white solid. Yield: 70%.
- IR (neat): 3405, 3120, 2805, 1455, 1435, 1375, 1330, 1245, 1225, 1085, 885, 865, 795 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 1.38 (d, J = 6.4 Hz, 3H, CH3), 4.20 (q, J = 6.4 Hz, 1H, CH), 5.51 (br s, 1H, OH), 7.15 (dd, J = 2.0 and 8.4 Hz, 1H, CH), 7.18 (s, 1H, NH), 7.26 (s, 1H, CH), 7.30 (d, J = 8.4 Hz, 1H, CH), 7.82 (d, J = 2.0 Hz, 1H, CH), 11.05 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 19.2 (CH3), 53.7 (CH), 110.7 (C), 113.2 (CH), 116.6 (C), 121.6 (CH), 123.1 (CH), 124.1 (CH), 128.2 (C), 134.9 (C) ppm. LRMS (ESI): m/z = 253 and 255 [(M-H)-].
- In a flask, the hydroxylamine (fb) (780 mg, 3.06 mmol) was dissolved in methanol (10 mL). A 20% wt. aqueous solution of TiCl3 (4.3 mL, 6.73 mmol) was added dropwise at room temperature. When the dark TiCl3 solution was added, the mixture became black but lost rapidly this dark color to become clear (due to the rapid reaction between TiCl3 and the hydroxylamine). After stirring for 30 minutes, the mixture was poured in a 20% wt. aqueous solution of NaOH saturated with NaCl. The resulting solution was extracted three times with ethyl acetate. The organics were washed with water and brine, dried over anhydrous MgSO4 and concentrated. The desired product (gb) was obtained without any further purification as a brown solid. Yield: 92%.
- 1H NMR (400 MHz, DMSO-d6): δ = 1.38 (d, J = 6.8 Hz, 3H, CH3), 2.16 (br s, 2H, NH2), 4.25 (q, J = 6.8 Hz, 1H, CH), 7.15 (dd, J = 1.6 and 8.6 Hz, 1H, CH), 7.23 (s, 1H, CH), 7.30 (d, J = 8.6 Hz, 1H, CH), 7.84 (s, 1H, CH), 11.00 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 25.0 (CH3), 43.4 (CH), 110.6 (C), 113.2 (CH), 119.2 (C), 121.4 (CH), 122.6 (CH), 123.1 (CH), 127.5 (C), 135.1 (C) ppm. LRMS (ESI: m/z = 237 and 239 [(M-H)-].
- In a dry flask under argon, the amine (gb) (100 mg, 0.42 mmol) and triethylamine (67 mg, 0.67 mmol) were dissolved in 3 mL of dry dichloromethane. After cooling this solution to 0 °C, the acid chloride (8b) (143 mg, 0.502 mmol) was added and the mixture was stirred at 0 °C for 30 minutes. The reaction was then quenched with an aqueous saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 1/1) to afford the desired product 5 (130 mg, 0.266 mmol) as a white solid. Yield: 63 %.
- Mp : 141 °C. IR (ATR): 3270, 2975, 1665, 1614, 1494, 1418, 1229, 1124 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 1.62 (d, J = 6.9 Hz, 3H, CH3), 5.34-5.44 (m, 1H, CH), 7.17 (d, J = 8.4 Hz, 1H, CH), 7.32-7.41 (m, 3H, CH), 7.52 (d, J = 8.4 Hz, 1H, CH), 7.86 (s, 1H, CH), 8.34 (d, J = 2.1 Hz, 1H, CH), 8.74 (s, 1H, CH), 8.94 (d, J = 8.8 Hz, 1H, NH), 11.15 (br s, 1H, NH), 12.41 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 20.3 (CH3), 40.6 (CH), 111.18 (C), 111.7 (C), 113.4 (CH), 114.6 (CH), 115.2 (C), 116.9 (C), 121.1 (CH), 123.2 (CH), 123.5 (CH), 124.1 (CH), 126.0 (CH), 127.5 (C), 127.8 (C), 134.97 (C), 135.03 (C), 139.1 (CH), 162.5 (C), 182.6 (C) ppm.
- A 1.0 M solution of SnCl4 (10 mL, 10.0 mmol) was added to a stirred solution of 5-bromoindole (ab) (980 mg, 5.0 mmol) and acetyl chloride (0.714 mL, 785 mg, 10.0 mmol) in 20 mL of dry toluene at 0 °C. The resulting mixture was stirred at room temperature during 4 hours, and then 50 mL of water was added. The mixture was extracted with EtOAc (3x20 mL) and the collected organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Column chromatography using EtOAc-pentane (from 5/95 to 80/20) yielded pure acetylindole (jb) (1.0 g, 4.2 mmol) as a white solid. Yield: 84%.
- 1H NMR (300 MHz, DMSO-d6): δ = 2.44 (s, 3H), 7.33 (dd, J = 2.0 and 8.6 Hz, 1H), 7.45 (dd, J = 0.4 and 8.6 Hz, 1H), 8.31 (dd, J = 0.4 and 2.0 Hz, 1H), 8.34 (s, 1H) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 27.1, 114.2, 114.5, 116.2, 123.4, 125.3, 127.0, 135.4, 135.5, 192.8 ppm.
- NH2OH.HCl (834 mg, 12.0 mmol) was added to a stirred solution of 3-acetyl-5-bromoindole (jb) (952 mg, 4.0 mmol) and pyridine (0.967 mL, 948 mg, 12.0 mmol) in 20 mL of ethanol. The resulting mixture was stirred at reflux for 2 hours and then ethanol was evaporated. Water (50 mL) was added and then the mixture was extracted with EtOAc (3x30 mL). The collected organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Pure oxime (kb) (1.0 g, 3.95 mmol) was obtained as a colorless oil. Yield: 99%.
- 1H NMR (300 MHz, CD3OD): δ = 2.22 (s, 3H), 7.18-7.28 (m, 2H), 7.45 (s, 1H), 8.37 (s, 1H) ppm.
- To a stirred and carefully deoxygenated solution of indolic oxime (kb) (633 mg, 2.5 mmol) and H2O (720 mg, 40.0 mmol, 16 equiv.) in 10 mL of THF, a 0.1 M solution of SmI2 (110 mL, 11.0 mmol, 4.4 equiv.) in THF was added at room temperature under argon. After 10 minutes, a saturated solution of Na2S2O3 (20 mL) and NaHCO3 (20 mL) then EtOAc (50 mL) were added. After extraction, the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Pure amine (gb) (560 mg, 2.34 mmol) was obtained as a white solid. Yield: 94%.
- 1H NMR (300 MHz, CDCl3): δ = 1.38 (d, J = 6.6 Hz, 3H), 2.50 (br s, 2H), 4.26 (q, J = 6.6 Hz, 1H), 6.88 (s, 1H), 6.9-7.02 (m, 1H), 7.09-7.12 (m, 1H), 7.66 (s, 1H), 9.00 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 24.3, 43.6, 112.3, 112.8, 121.2, 121.4, 121.5, 124.6, 127.5, 135.1 ppm.
- In a dry flask under argon, the [2-amino-2-(5-bromo-1H-indol-3-yl)ethyl]carbamic acid tert-butyl ester (1b) (60 mg, 0.17 mmol) and triethylamine (0.028 mL, 0.20 mmol) were dissolved in 2 mL of dry dichloromethane. After cooling this solution to 0 °C, benzoyl chloride (0.020 mL, 0.17 mmol) was added dropwise and the mixture was stirred at 0 °C for 15 minutes.
- The reaction was then quenched with water and diluted with ethyl acetate. The organic layer was washed with a 1M aqueous solution of HCl and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 1/1 then 7/3). After recrystallization in a mixture of ethyl acetate and pentane, the desired product 12 (45 mg, 0.098 mmol) was obtained as a white solid. Yield: 58 %.
- Mp: 187 °C. IR (ATR): 3375, 3310, 1661, 1629, 1519, 1276, 1163 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 1.33 (s, 9H, CH3), 3.44-3.52 (m, 2H, CH2), 5.42-5.49 (m, 1H, CH), 7.00 (t, J = 5.8 Hz, 1H, NH), 7.17 (d, J = 6.4 Hz, 1H, CH), 7.32 (d, J = 8.8 Hz, 1H, CH), 7.38 (s, 1H, CH), 7.44 (t, J = 7.2 Hz, 2H, CH), 7.51 (t, J = 7.2 Hz, 1H, CH), 7.82-7.88 (m, 3H, CH and NH), 8.55 (d, J = 8.8 Hz, 1H, CH), 11.14 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 28.1 (CH3), 44.1 (CH2), 46.2 (CH), 77.6 (C), 111.1 (C), 113.3 (CH), 114.5 (C), 121.0 (CH), 123.4 (CH), 124.2 (CH), 127.3 (CH), 128.0 (CH), 130.9 (CH), 134.61 (C), 134.65 (C), 134.71 (C), 155.8 (C), 165.8 (C) ppm. LRMS (ESI): m/z = 480 and 482 [(M+Na)+].
- In a dry flask under argon, 4-bromophenylacetic acid (860 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 °C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The desired acid chloride was obtained and dissolved in 4 mL of dichloromethane to make a 1M solution.
- In a dry flask under argon, the [2-amino-2-(5-bromo-1H-indol-3-yl)ethyl]carbamic acid tert-butyl ester (1b) (60 mg, 0.17 mmol) and triethylamine (0.033 mL, 0.24 mmol) were dissolved in 1 mL of dry dichloromethane. After cooling this solution to 0 °C, the 1M solution of 2-(4-bromophenyl)acetyl chloride previously obtained (0.204 mL, 0.204 mmol) was added dropwise and the mixture was stirred at 0 °C for one hour. The reaction was then quenched with water and diluted with ethyl acetate. The organic layer was washed with a 1M aqueous solution of HCl and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 1/1 then 8/2). After recrystallization in a mixture of ethyl acetate and pentane, the desired product 12a (50 mg, 0.09 mmol) was obtained as a white solid. Yield: 54 %.
- Mp: 131 °C. IR (ATR): 3425, 3338, 1678, 1634, 1533, 1488, 1458, 1276, 1169 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 1.34 (s, 9H, CH3), 3.29-3.43 (m, 2H, CH2), 3.41 (s, 2H, CH2), 5.17-5.23 (m, 1H, CH), 6.82 (t, J = 6.0 Hz, 1H, NH), 7.17 (dd, J = 1.6 and 8.4 Hz, 1H, CH), 7.21 (d, J = 8.4 Hz, 2H, CH), 7.29-7.31 (m, 2H, CH), 7.45 (d, J = 8.4 Hz, 2H, CH), 7.66 (s, 1H, CH), 8.30 (d, J = 8.8 Hz, 1H, NH), 11.13 (br s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 29.1 (CH3), 42.6 (CH2), 45.1 (CH2), 46.3 (CH), 78.6 (C), 112.1 (C), 114.3 (CH), 115.2 (C), 120.4 (C), 122.0 (CH), 124.5 (CH), 124.8 (CH), 128.9 (C), 131.9 (CH), 132.1 (CH), 135.8 (C), 136.8 (C), 156.6 (C), 170.0 (C) ppm. LRMS (ESI): m/z = 572, 574 and 576 and [(M+Na)+].
- In a dry flask under argon, the [2-amino-2-(5-bromo-1H-indol-3-yl)ethyl]carbamic acid tert-butyl ester (1b) (80 mg, 0.226 mmol) and triethylamine (0.063 mL, 0.452 mmol) were dissolved in 2 mL of dry dichloromethane. After cooling this solution to 0 °C, trifluoroacetic anhydride (0.035 mL, 0.248 mmol) was added and the mixture was stirred at 0 °C for 15 minutes. The reaction was then quenched with an aqueous saturated solution of NaHCO3 and diluted with dichloromethane. The organic layer was washed with saturated NaHCO3, 1M aqueous HCl and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, 3/7) to afford the desired product 13 (70 mg, 0.156 mmol) as a white solid. Yield: 69 %.
- IR (ATR): 3441, 3323, 1676, 1533, 1457, 1275, 1162 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 1.36 (s, 9H, CH3), 3.43-3.48 (m, 2H, CH2), 5.25-5.32 (m, 1H, CH), 7.03 (t, J = 5.7 Hz, 1H, NH), 7.20 (dd, J = 2.0 and 8.7 Hz, 1H, CH), 7.34 (d, J = 8.7 Hz, 1H, CH), 7.38 (d, J = 2.0 Hz, 1H, CH), 7.72 (s, 1H, CH), 9.63 (d, J = 8.7 Hz, 1H, NH), 11.24 (br s, 1H, NH) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 28.0 (CH3), 43.4 (CH2), 46.6 (CH), 77.8 (C), 111.4 (C), 112.3 (C), 133.5 (CH), 120.6 (CH), 123.7 (CH), 127.7 (CH), 155.9 (CF3, J C-F = 288.8 Hz), 127.7 (C), 134.7 (C), 155.6 (C, J C-F = 15.8 Hz), 156.0 (C) ppm. LRMS (ESI): m/z = 472 and 474 [(M+Na)+].
- In a dry flask under argon, nicotinic acid (492 mg, 4 mmol) was dissolved in dry dichloromethane (30 mL) and few drops of dry DMF. The sluggish solution was cooled to 0 °C and freshly distilled oxalyl chloride (0.412 mL, 4.8 mmol) was added dropwise. The mixture was then stirred for 2 hours at room temperature and directly evaporated under reduced pressure. The solid was washed with pentane and dried under vacuum. The desired nicotinoyl chloride hydrochloride was obtained as a white solid and used straightaway.
- In a dry flask under argon, the [2-amino-2-(5-bromo-1H-indol-3-yl)ethyl]carbamic acid tert-butyl ester (1b) (80 mg, 0.226 mmol) and triethylamine (0.094 mL, 0.68 mmol) were dissolved in 2 mL of dry dichloromethane. After cooling this solution to 0 °C, the nicotinoyl chloride hydrochloride previously obtained (48 mg, 0.271 mmol) was added and the mixture was stirred at 0 °C for 30 minutes. The reaction was then quenched with water and diluted with ethyl acetate. The organic layer was washed with a 1M aqueous solution of HCl and water, dried over anhydrous MgSO4 and concentrated. The crude material was purified by flash chromatography (EtOAc/pentane, from 1/1 to EtOAc). After recrystallization in a mixture of ethyl acetate and pentane, the desired product 14 (60 mg, 0.131 mmol) was obtained as a white solid. Yield: 58 %. Mp: 195 °C. IR (ATR): 3325, 3209, 2972, 1682, 1634, 1544, 1272, 1167 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 1.32 (s, 9H, CH3), 3.46-3.50 (m, 2H, CH2), 5.43-5.49 (m, 1H, CH), 7.03 (t, J = 6.0 Hz, 1H, NH), 7.18 (d, J = 8.4 Hz, 1H, CH), 7.32 (d, J = 8.4 Hz, 1H, CH), 7.40 (s, 1H, CH), 7.49 (dd, J = 4.8 and 8.0 Hz, 1H, CH), 7.83 (s, 1H, CH), 8.19 (d, J = 8.0 Hz, 1H, CH), 8.68 8 (d, J = 3.6 Hz, 1H, CH), 8.77 (d, J = 8.8 Hz, 1H, NH), 9.02 (s, 1H, CH), 11.16 (s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 29.1 (CH3), 45.1 (CH2), 47.3 (CH3), 78.6 (C), 112.2 (C), 114.4 (CH), 115.1 (C), 121.9 (CH), 124.2 (CH), 124.4 (CH), 125.3 (CH), 129.0 (C), 131.1 (C), 135.7 (C), 136.0 (CH), 149.5 (CH), 152.6 (CH), 156.8 (C), 165.4 (C) ppm. LRMS (ESI): m/z = 459 and 461 [(M+H)+].
- To a stirred suspension of methyltrioxorhenium (MTO) (6 mg, 0.025 mmol) and urea hydrogen peroxide (UHP) (4.7 g, 50.0 mmol) in dichloromethane (100 mL), 1 mL of MeOH was added at room temperature. Within 15 min the yellow colour appeared, the reaction mixture was cooled in an ice bath and cyclic amine (piperidine, morpholine or (N-Boc)pyperazine) (5.0 mmol) was added in one portion, the yellow color disappeared. The ice bath was removed and another portion of MTO (6 mg, 0.025 mmol) was added at room temperature. The color of reaction mixture turned pale yellow. After 5 minutes of stirring, the excess of UHP was filtered off. Dichloromethane and MeOH were evaporated under reduced pressure. The residue was diluted with dichloromethane (100 mL), a solid substance was filtered off and the filtrate was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure till 50 ml. The nitrone solution 9a-c was used for the next step without any purification.
- A cold solution of hydrochloric acid was prepared by reaction of freshly distilled acetyl chloride (0.714 ml, 785 mg, 10.0 mmol) with 5 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was added to a solution of both nitrone 9a-c (5.0 mmol) and indole (aa or ab) (5.0 mmol) in 15 mL of dry methanol and 50 ml of dry dichloromethane. The reaction mixture was stirred at 0 °C during 2 hours to completion. A saturated aqueous solution of NaHCO3 was then added. The mixture was extracted with dichloromethane (3x20 mL) and the collected organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
- Column chromatography using EtOAc-pentane (10/90 - 80/20) yielded pure N-hydroxylamines 10a-f as white solids.
-
- The compound 10a (840 mg, 3.89 mmol) was obtained from piperidine (425 mg, 5.0 mmol) and indole (aa) (585 mg, 5.0 mmol). Yield: 78%.
- IR (neat): 3300, 2925, 2855, 2830, 1445, 1335, 1315, 1225, 1095, 1065, 1035, 1010, 870, 775, 730 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.31-1.68 (m, 1H), 1.72-1.81 (m, 3H), 1.86-1.92 (m, 2H), 2.61 (dt, J = 3.8 and 10.9 Hz, 1H), 3.34 (d, J = 11.4 Hz, 1H), 3.69 (dd, J = 6.5 and 8.2 Hz, 1H), 5.59 (br s, 1H), 6.98 (d, J = 2.4 Hz, 1H), 7.09 (ddd, J = 1.2, 7.1 and 7.8 Hz, 1H), 7.17 (ddd, J = 1.2, 7.1 and 8.1 Hz, 1H), 7.30 (dt, J = 1.2 and 8.1 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 8.10 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 24.3, 25.9, 33.9, 59.1, 65.9,111.1, 117.9, 119.3, 120.0, 121.9, 122.1, 126.8, 136.2 ppm. LRMS (ESI): m/z (%) = 217 (100) [(M+H)+].
-
- The compound 10b (890 mg, 4.08 mmol) was obtained from morpholine (435 mg, 5.0 mmol) and indole (aa) (585 mg, 5.0 mmol). Yield: 82%.
- IR (neat): 3340, 2920, 2855, 1455, 1435, 1340, 1435, 1340, 1300, 1220, 1100, 1085, 965, 875, 745 cm-1. 1H NMR (300 MHz, CDCl3-CD3OD): δ = 2.88 (td, J = 3.6 and 11.5 Hz, 1H), 3.21 (d, J = 10.9 Hz, 1H), 3.65-3.96 (m, 5H), 7.02-7.15 (m, 2H), 7.16 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H) ppm. 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 57.7, 64.8, 66.3, 71.1, 111.0, 111.3, 118.7, 118.8, 121.2, 122.8, 126.4, 136.1 ppm. LRMS (ESI): m/z (%) = 219 (100) [(M+H)+], 201 (18) [(M-H2O+H)+].
-
- The compound 10c (1.208 g, 3.81 mmol) was obtained from N-Boc-piperazine (930 mg, 5.0 mmol) and indole (aa) (585 mg, 5.0 mmol). Yield: 76%.
- IR (neat): 3305, 2915, 2885, 1740, 1660, 1615, 1455, 1430, 1365, 1280, 1250, 1165, 1135, 1015, 745 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.47 (s, 9H), 2.61-2.74 (m, 1H), 3.08-3.20 (m, 2H), 3.23-3.30 (m, 1H), 3.71-3.79 (m, 1H), 4.06-4.13 (m, 2H), 7.01 (ddd, J = 1.2, 7.8 and 9.0 Hz, 1H), 7.10 (ddd, J = 1.2, 7.0 and 9.3 Hz, 1H), 7.25 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.7 (3C), 58.5, 58.8, 61.6, 65.7, 81.5 (C), 112.3, 114.3, 119.9, 120.2, 122.5, 124.1, 128.1, 138.1, 156.2 ppm. LRMS (ESI): m/z (%) = 340 (22) [(M+Na)+], 318 (42) [(M+H)+], 262 (100) [(M - t-Bu+H)+].
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- The compound 10d (915 mg, 3.10 mmol) was obtained from piperidine (425 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 62%.
- IR (neat): 3280, 2940, 2920, 2855, 2825, 1465, 1445, 1315, 1250, 1225, 1120, 1095, 1060, 1035, 880, 790, 775, 760 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.33-1.52 (m, 1H), 1.68-1.98 (m, 5H), 2.65 (td, J = 4.1 and 10.8 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.63 (dd, J = 6.5 and 8.2 Hz, 1H), 7.15 (dd, J = 1.9 and 8.6 Hz, 1H), 7.22 (s, 1H), 7.25 (dd, J = 0.5 and 8.6 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 25.5, 27.0, 35.0, 60.9, 67.0, 112.8, 113.8, 118.1, 123.2, 124.9, 125.1, 130.3, 136.7 ppm. LRMS (ESI): m/z (%) = 295 (100) and 297 (95) [(M+H)+].
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- The compound 10e (1.13 g, 3.79 mmol) was obtained from morpholine (435 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 76%.
- IR (neat): 3310, 2885, 2860, 1465, 1330, 1295, 1100, 1055, 1045, 965, 875, 780, 745 cm-1 1H NMR (300 MHz, CDCl3-CD3OD): δ = 2.86 (td, J = 3.6 and 11.5 Hz, 1H), 3.23 (d, J = 10.9 Hz, 1H), 3.62-3.97 (m, 5H), 7.16-7.24 (m, 3H), 7.92 (d, J = 1.3 Hz, 1H) ppm. 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 57.8, 64.6, 66.3, 70.9, 111.1, 111.8, 112.4, 121.4, 123.9, 124.1, 128.1, 134.7 ppm. LRMS (ESI): m/z (%) = 297 (100) and 299 (95) [(M+H)+].
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- The compound 10f (1.03 g, 2.61 mmol) was obtained from (N-Boc)piperazine (930 mg, 5.0 mmol) and 5-bromoindole (ab) (980 mg, 5.0 mmol). Yield: 52%.
- IR (neat): 3290, 2970, 2920, 2855, 1655, 1430, 1365, 1270, 1250, 1165, 1135, 1110, 880, 865, 785 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.48 (s, 9H), 2.65-2.72 (m, 1H), 3.08-3.18 (m, 2H), 3.30-3.34 (m, 1H), 3.67-3.71 (m, 1H), 4.05-4.14 (m, 2H), 7.18 (dd, J = 1.9 and 8.7 Hz, 1H), 7.27 (dd, J = 0.6 and 8.7 Hz, 1H), 7.28 (s, 1H), 7.90 (s, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.7 (3C), 49.3, 49.5, 58.9, 65.5, 81.6 (C), 113.1, 114.0, 114.3, 123.0, 125.2, 125.7, 129.8, 136.8, 156.2 ppm. LRMS (ESI): m/z = 418 and 420 [(M+Na)+], 396 and 398 [(M+H)+].
- To a stirred solution of each indolic N-hydroxylamine 10a-f (1.0 mmol) in 5 mL of methanol was added 1.7 g of a 20% aqueous solution of titanium trichloride (339 mg, 2.2 mmol). The resulting mixture was stirred at room temperature during 30 min. A large excess of an aqueous 20% NaOH solution saturated with NaCl was added. Methanol was then removed under vacuum and the crude mixture was extracted with ethyl acetate (3x20 mL). Combined organic layers were washed with H2O, brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
- Pure amines 11a-f were obtained as white solids and were used without purification.
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- The compound 11a (200 mg, 1 mmol) was obtained from N-hydroxylamine 10a (216 mg, 1.0 mmol). Yield: 100%.
- IR (neat): 3160, 2940, 2925, 1590, 1450, 1440, 1430, 1340, 1230, 1105, 1000, 745 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.73-2.06 (m, 4H), 2.12-2.20 (m, 2H), 3.20 (td, J = 3.6 and 12.5 Hz, 1H), 3.35-3.42 (m, 1H), 4.50-4.5 5 (m, 1H), 7.11 (td, J = 1.3 and 7.9 Hz, 1H), 7.17 (td, J = 1.3 and 7.1 Hz, 1H), 7.42 (dt, J = 0.8 and 7.9 Hz, 1H), 7.47 (s, 1H), 7.73 (dt, J = 0.8 and 7.7 Hz, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 23.6, 24.4, 31.5, 46.7, 54.8, 112.8, 113.1, 119.2, 120.7, 123.3, 124.7, 126.8, 137.9 ppm. LRMS (ESI): m/z (%) = 201 (100) [(M+H)+].
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- The compound 11b (200 mg, 0.99 mmol) was obtained from N-hydroxylamine 10b (218 mg, 1.0 mmol). Yield: 99%.
- IR (neat): 3405, 3280, 2970, 2855, 1550, 1450, 1440, 1340, 1225, 1100, 930, 865, 840, 740 cm-1 . 1H NMR (300 MHz, CDCl3): δ = 1.99-2.16 (br s, 1H), 3.00 (dt, J = 2.2 and 11.9 Hz, 1H), 3.15 (td, J = 3.3 and 11.1 Hz, 1H), 3.55 (dd, J = 9.9 and 11.1 Hz, 1H), 3.68 (td, J = 2.7 and 11.1 Hz, 1H), 3.86-3.95 (m, 1H), 4.02 (dd, J = 3.1 and 11.1 Hz, 1H), 4.30 (dd, J = 3.1 and 9.9 Hz, 1H), 7.08-7.21 (m, 3H), 7.28-7.31 (m, 1H), 7.69-7.73 (m, 1H), 8.53 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 46.7, 53.1, 67.3, 73.1, 111.2, 115.5, 118.9, 119.5, 121.5, 122.1, 126.1, 136.1 ppm. LRMS (ESI): m/z (%) = 203 (100) [(M+H)+].
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- The compound 11c (283 mg, 0.94 mmol) was obtained from N-hydroxylamine 10c (317 mg, 1.0 mmol). Yield: 94%.
- IR (neat): 3325, 2905, 2855, 2800, 1670, 1455, 1440, 1400, 1365, 1270, 1245, 1165, 1020, 740 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.48 (s, 9H), 2.81-3.05 (m, 4H), 4.00-4.05 (m, 2H), 4.24 (d, J = 12.7 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H) ppm. 13C NMR (75 MHz, CD3OD): δ = 28.8 (3C), 46.7, 48.8, 49.3, 53.9, 81.4 (C), 112.5, 115.7, 119.3, 120.1, 122.8 (2C), 127.3, 138.0, 156.4 ppm. LRMS (ESI): m/z (%) = 302 (57) [(M+H)+], 246 (100) [(M - t-Bu+H)+].
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- The compound 11d (279 mg, 1 mmol) was obtained from N-hydroxylamine 10d (295 mg, 1.0 mmol). Yield: 100%.
- IR (neat): 3195, 2925, 2805, 1455, 1435, 1320, 1300, 1225, 1115, 1100, 885, 865, 785 cm-1. 1H NMR (300 MHz, CDCl3-CD3OD): δ = 1.55-1.81 (m, 4H), 1.90-2.08 (m, 2H), 2.88 (td, J = 3.1 and 11.8 Hz, 1H), 3.22 (d, J = 11.8 Hz, 1H), 3.96-4.00 (m, 1H), 4.00 (br s, 1H), 7.20-7.38 (m, 3H), 7.73-7.74 (m, 1H) ppm. 13C NMR (75.5 MHz, CDCl3-CD3OD): δ = 24.5, 24.6, 32.5, 46.8, 53.5, 112.1, 112.8, 116.6, 120.5, 122.8, 124.3, 127.3, 134.7 ppm. LRMS (ESI): m/z (%) = 279 (100) and 281 (100) [(M+H)+].
-
- The compound 11e (280 mg, 1 mmol) was obtained from N-hydroxylamine 10e (297 mg, 1.0 mmol). Yield: 100%.
- IR (neat): 3295, 2960, 2915, 2855, 1455, 1435, 1285, 1205, 1100, 1065, 1020, 875, 805, 775 cm-1. 1H NMR (300 MHz, CDCl3-CD3OD): δ = 2.99 (dt, J = 2.2 and 11.8 Hz, 1H), 3.08 (br s, 1H), 3.13 (ddd, J = 3.2, 11.1 and 12.1 Hz, 1H), 3.53 (dd, J = 10.0 and 11.2 Hz, 1H), 3.68 (td, J = 2.8 and 11.1 Hz, 1H), 3.87-3.94 (m, 1H), 3.96 (dd, J = 3.2 and 11.2 Hz, 1H), 4.21 (dd, J = 2.8 and 10.0 Hz, 1H), 7.18-7.26 (m, 3H), 7.79-7.80 (m, 1H) ppm. 13C NMR (75.5 MHz, CDCl3 -CD3OD): δ = 46.2, 52.5, 66.9, 72.5, 112.4, 112.8, 113.8, 121.1, 123.0, 124.7, 127.6, 134.7 ppm. LRMS (ESI): m/z (%) = 281 (100) and 283 (95) [(M+H)+].
-
- The compound 11f (375 mg, 0.99 mmol) was obtained from N-hydroxylamine 10f (396 mg, 1.0 mmol). Yield: 99%.
- IR (neat): 3280, 2970, 2905, 2865, 1665, 1455, 1425, 1365, 1245, 1165, 1125, 880, 860 795 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.50 (s, 9H), 2.08-2.16 (br s, 1H), 2.87-3.08 (m, 4H), 3.96-4.19 (m, 3H), 7.10 (br s, 1H), 7.16-7.26 (m, 2H), 7.87 (s, 1H), 8.85 (br s, 1H) ppm. 13C NMR 75.5 MHz, CDCl3): δ = 28.5 (3C), 46.0, 48.5, 48.8, 52.8, 79.9 (C), 112.7, 112.8, 116.0, 121.8, 122.6, 124.9, 127.7, 134.9, 154.9 ppm. LRMS (ESI): m/z (%) = 380 (25) and 382 (25) [(M+H)+], 324 (100) and 326 (95) [M - t-Bu+H)+].
- To a stirred solution of indolic amine 11a-f (1.0 mmol) in 5 mL of dry dichloromethane, indolic oxoacetyl chloride (8a) or (8b) (1.2 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature during 1 hour. A saturated aqueous solution of NaHCO3 was then added. The mixture was extracted with EtOAc (3x20 mL) and the collected organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum.
- Column chromatography using EtOAc-pentane (from 10/90 to80/20) yielded pure bis-indole 6a-f as a beige foam.
-
- The compound 6a (205 mg, 0.55 mmol) was obtained from amine 11a (200 mg, 1.0 mmol) and oxoacetyl chloride (8a) (249 mg, 1.2 mmol). Yield: 55%.
- IR (neat): 3270, 2930, 2850, 1600, 1520, 1460, 1420, 1240, 1125, 945, 740 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.40-1.68 (m, 4H), 1.70-1.82 (m, 1H), 2.23 (d, J = 13.4 Hz, 1H), 2.95-3.01 (m, 1H), 3.40 (d, J = 13.4 Hz, 1H), 6.16 (d, J = 4.8 Hz, 1H), 6.92-7.19 (m, 6H), 7.23-7.25 (m, 2H), 7.69-7.75 (m, 2H), 8.16-8.21 (m, 1H), 9.23 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.3, 30.4, 32.3, 46.9, 49.8, 115.3, 116.1, 117.1, 117.9, 123.3, 125.7, 126.0, 126.9, 127.2, 127.4, 128.0, 129.1, 130.3, 139.9, 140.4, 140.5, 140.8, 170.8, 190.7 ppm. LRMS (ESI): m/z (%) = 394 (100) [(M+Na)+].
-
- The compound 6b (230 mg, 0.617 mmol) was obtained from amine 11b (202 mg, 1.0 mmol) and oxoacetyl chloride (8a) (249 mg, 1.2 mmol). Yield: 62%.
- IR (neat): 3270, 2960, 2920, 2840, 1605, 1520, 1455, 1420, 1240, 1115, 1060, 940, 740 cm-1. 1H NMR (300 MHz, CD3OD): δ = 3.28-3.39 (m, 2H), 3.60 (td, J = 3.4 and 11.3 Hz, 1H), 3.81 (dd, J = 2.4 and 11.7 Hz, 1H), 3.99 (dd, J = 3.4 and 11.7 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H), 5.96 (d, J = 2.7 Hz, 1H), 7.10 (t, J = 7.1 Hz, 1H), 7.17 (t, J = 7.1 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 7.42 (dd, J= 2.4 and 8.0 Hz, 1H), 7.61 (s, 1H), 7.75 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 43.6, 46.9, 68.5, 71.3, 112.5, 112.9, 113.3, 114.9, 120.3, 120.4, 122.5, 123.0, 124.1, 125.2, 126.4, 126.5, 127.9, 137.7, 137.8, 138.6, 167.9, 187.5 ppm. LRMS (ESI): m/z (%) = 396 (100) [(M+Na)+].
-
- The compound 6c (195 mg, 0.413 mmol) was obtained from amine 11c (301 mg, 1.0 mmol) and oxoacetyl chloride (8a) (249 mg, 1.2 mmol). Yield: 41%.
- IR (neat): 3360, 2970, 2920, 2865, 1675, 1610, 1585, 1460, 1430, 1365, 1245, 1155, 1120, 935, 740 cm-1. 1H NMR (300 MHz, CD3OD): δ = 1.42 (s, 9H), 2.87-3.52 (m, 4H), 3.98 (d, J = 12.2 Hz, 1H), 4.58-4.72 (m, 1H), 6.13 (br s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 2H), 7.16-7.25 (m, 3H), 7.38-7.44 (m, 2H), 7.81 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 28.7 (3C), 47.2, 48.9, 49.1, 49.3, 81.9 (C), 112.6, 113.4, 115.0, 120.2, 120.5, 122.6, 123.2, 124.1, 125.1, 125.3, 126.5, 127.0, 127.7, 137.9, 138.1, 138.7, 156.2, 167.8, 187.4 ppm. LRMS (ESI): m/z (%) = 495 (100) [(M+Na)+], 373 (35) [(M - Boc+H)+].
-
- The compound 6d (410 mg, 0.775 mmol) was obtained from amine 11d (279 mg, 1.0 mmol) and oxoacetyl chloride (8b) (344 mg, 1.2 mmol). Yield: 78%.
- IR (neat): 3170, 2940, 1610, 1520, 1445, 1430, 1230, 950, 885, 810, 805, 675 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 1.35-1.59 (m, 2H), 1.60-1.82 (m, 2H), 1.84-2.08 (m, 2H), 2.32-2.36 (m, 1H), 2.85-2.95 (m, 1H), 6.03 (d, J= 4.3 Hz, 1H), 7.24 (dd, J= 1.9 and 8.6 Hz, 1H), 7.37-7.45 (m, 2H), 7.50-7.54 (m, 2H), 7.83 (d, J = 1.9 Hz, 1H), 8.16 (s, 1H), 8.25-8.28 (m, 2H), 11.32 (br s, 1H). 13C NMR (75.5 MHz, DMSO-d6): δ = 20.5, 26.4, 28.2, 42.6, 45.2, 112.1, 112.5, 113.1, 114.1, 115.3, 115.8, 121.7, 123.6, 124.3, 126.4, 126.8, 127.1, 128.5, 135.5, 136.2, 137.6, 166.0, 186.7 ppm. LRMS (ESI): m/z (%) = 550 (42), 552 (84) and 554 (42) [(M+Na)+], 304 (100) and 306 (100) [(M - C10H5BrO2+Na)+].
-
- The compound 6e (380 mg, 0.716 mmol) was obtained from amine 11e (281 mg, 1.0 mmol) and oxoacetyl chloride (8b) (344 mg, 1.2 mmol). Yield: 72%.
- IR (neat): 3290, 2900, 2865, 1635, 1615, 1520, 1445, 1420, 1295, 1230, 1145, 1100, 940, 880, 790, 745 cm-1. 1H NMR (300 MHz, DMSO-d6): δ = 3.22-3.29 (m, 1H), 3.48 (td, J = 3.0 and 11.2 Hz, 1H), 3.83 (dd, J= 2.5 and 11.2 Hz, 1H), 3.99 (dd, J= 3.5 and 11.8 Hz, 1H), 4.07-4.14 (m, 1H), 4.36 (d, J = 11.8 Hz, 1H), 5.78 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 1.9 and 8.6 Hz, 1H), 7.39-7.44 (m, 2H), 7.50 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 8.09 (s, 1H), 8.23 (d, J = 1.7 Hz, 1H), 11.35 (br s, 1H), 12.53 (br s, 1H) ppm. 13C NMR (75.5 MHz, DMSO-d6): δ = 41.9, 44.4, 66.8, 69.4, 111.3, 111.6, 112.6, 113.6, 114.7, 115.3, 121.2, 123.0, 123.8, 126.3, 126.6, 126.8, 128.1, 134.6, 135.6, 137.4, 165.0, 185.4 ppm. LRMS (ESI): m/z (%) = 552, 554 (100) and 556 [(M+Na)+], 530, 532 (29) and 534 [(M+H)+].
-
- The compound 6f (416 mg, 0.66 mmol) was obtained from amine 11f (380 mg, 1.0 mmol) and oxoacetyl chloride (8b) (344 mg, 1.2 mmol). Yield: 66%.
- IR (neat): 3275, 2970, 2925, 2855, 1675, 1615, 1445, 1420, 1365, 1235, 1160, 1125, 885 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 9H), 2.81-2.99 (m, 2H), 3.17-3.41 (m, 2H), 3.78-3.85 (m, 1H), 4.43-4.59 (m, 1H), 5.90 (br s, 1H), 6.91-7.19 (m, 6H), 7.79 (s, 1H), 8.26 (s, 1H), 8.68 (br s, 1H), 10.04 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.4 (3C), 41.7, 41.3, 45.7, 60.5, 80.9 (C), 111.5, 112.9, 113.0, 113.2, 113.4, 113.9, 116.9, 121.7, 124.5, 125.2, 126.8, 127.3, 127.9, 134.9, 135.2, 136.5, 154.7, 166.0, 185.0 ppm. LRMS (ESI): m/z (%) = 651, 653 (100) and 655 [(M+Na)+].
-
- A cold solution of hydrochloric acid was prepared by reaction of freshly distilled acetyl chloride (0.143 mL, 157 mg, 2.0 mmol) with 3 mL of dry methanol. This solution was stirred at 0 °C during 15 min and was then added to a solution of bis-indole 6f (126 mg, 0.2 mmol) in 2 mL of dry methanol. The resulting mixture was stirred during 2 hours at room temperature. Methanol was then slowly evaporated under vacuum (t <20°C) till 1 mL. The saturated solution then was added dropwise to 50 mL of ether and the solid precipitate was filtered off and dried under vacuum. The bis-indolic amine salt 7 (80 mg, 0.14 mmol) was obtained as a rose-grey solid. Yield: 71%.
- IR (neat): 3205, 2930, 1615, 1445, 1425, 1230, 1145, 1105, 885, 780 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.78-2.92 (m, 2H), 3.08-3.37 (m, 2H), 3.81-3.89 (m, 1H), 4.36-4.55 (m, 1H), 5.92 (br s, 1H), 6.81-7.07 (m, 6H), 7.79 (s, 1H), 8.27 (s, 1H), 8.70 (br s, 1H), 10.05 (br s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 41.3, 41.4, 45.3, 60.1, 110.8, 112.0, 112.6, 112.8, 113.0, 113.5, 116.5, 121.3, 124.1, 124.8, 126.4, 126.9, 127.5, 134.5, 134.8, 136.1, 165.6, 184.6 ppm. LRMS (ESI): m/z (%) = 529, 531 (100) and 533 [(M+H)+].
- The microdilution method recommended by the Clinical and Laboratory Standard Institute [M07-A8, Vol.29, N°2] was used. The activity of indolic compounds was tested against 28 bacterial strains belonging to 17 different species and 12 different genera (Staphylococcus, Streptococcus, Enterococcus, Listeria, Bacillus, Haemophilus, Escherichia, Klebsiella, Enterobacter, Serratia, Pseudomonas, and Acinetobacter). Bacterial inocula were prepared in Mueller Hinton broth (MH2, bioMérieux, Marcy L'Etoile, France), supplemented with 10% sheep blood for fastidious species (i.e., Streptococcus pneumoniae and Haemophilus influenzae). They were dispensed in 96 well microtiter plates (5 x 105 CFU/ml of final inoculum). Indolic compounds were added to the wells as to obtain two-fold serial concentrations (0.25-64 mg/L of final concentrations). Plates were incubated at 37 °C in ambient air, or at 37 °C in 5% CO2 enriched atmosphere for fastidious species. MICs were read after 18 hours incubation of cultures, and corresponded to the minimum indolic compound concentration that allowed complete visual growth inhibition of bacteria. Drug-free cultures served as growth controls. Cultures receiving gentamicin, ciprofloxacin or cefotaxime served as positive controls.
- The results are given in the following Table I:
- Compounds of the invention present a strong intrinsic antibacterial activity, in particular against Staphylococcus aureus and Staphylococcus epidermidis.
- Further, compounds of the invention present an anti-Staphylococcus activity even against strains presenting an acquired resistance to beta-lactams, including methicillin-resistant Staphylococcus aureus (MRSA) strains such as CIP65.25 (MetiR) and ATCC 33592 (MetiR), and/or to glycopeptides such as the VISA (vancomycin-intermediate S. aureus) strain ATCC 106414. These multi-resistant bacterial strains are frequently implicated in severe hospital infections.
- The lack of intrinsic antibacterial activity of compounds 12, 12a, 13 and 14 shows that the presence of the bis-indoles moieties is essential for the antibacterial activity of the compounds of the invention.
TABLE I Compound 2 3 4 5 6a 6b 6c 6d 6f 12 12a 13 14 Staphylococcus (Micrococcaceae Gram+) S. aureus ATCC 25923 >128 4 1.6 1 >128 >128 >128 >128 >128 >128 >128 (>32) >128 >128 S. aureus ATCC 29213 >128 2 0.8 1 >128 >128 >128 2-4 2-4 >128 >32 128 64 S. aureus ATCC 9144 >128 4 0.8 1 >128 >128 >128 >128 >128 >128 >32 >128 >128 S. aureus ATCC 6538 >128 4 0.8 1 >128 >128 >128 >128 >128 >128 >32 64 128 S. aureus CIP 65.6 >128 4 0.8 2 >128 >128 >128 >128 >128 >128 >32 >128 128 S. aureus CIP 103428 >128 4 1.6 1 >128 >128 >128 >128 >128 >128 >32 64 128 S. aureus CIP 65.25 (MetiR) >128 4 1.6 1 >128 >128 >128 >128 >128 >128 >32 >128 128 S. aureus ATCC 33592 (MetiR) >128 4 0.8 1 >128 >128 >128 >128 >128 >128 >32 >128 128 S. aureus ATCC 106414 (VISA) >128 4 0.8 1 >128 >128 >128 >128 >128 >128 >32 >128 128 S. epidermidis ATCC 12228 >128 4 0.8 2 >128 >128 >128 >128 >128 >128 >32 >128 >128 S. epidermidis CIP 81.55 >128 8 1.6 2 >128 >128 >128 >128 >128 >128 >32 >128 >128 S. epidermidis CIP 103627 >128 >16 1.6 2 >128 >128 >128 >128 >128 >128 >32 >128 >128 S. aureus SA-1199B >128 4 1.6 2 >128 >128 >128 >128 >128 >128 >32 64 128 Streptococcus (Streptococcaceae Gram+) Streptococcus pneumoniae ATCC 49619 >128 >128 - 32 >128 >128 >128 >128 >128 >128 128 >128 Streptococcus pneumoniae ATCC 6303 >128 64 - 32 >128 >128 >128 >128 >128 >128 128 128 >128 Streptococcus B ATCC 12400 >128 64 - 64 >128 >128 >128 >128 >128 >128 64 128 >128 Streptococcus A (pyogenes) CIP 104226 >128 128 - 32 >128 >128 >128 >128 >128 >128 >128 128 >128 Streptococcus mitis CIP 103335 >128 >128 - 64 >128 >128 >128 >128 >128 >128 >128 >128 >128 Enterococcus faecium CIP 54.32 >128 32 - 64 >128 >128 >128 >128 >128 >128 >128 >128 >128 Enterococcus faecalis ATCC 29212 >128 >128 - 128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Listeria (Listeriaceae Gram+) Listeria innocua CIP 80.11 >128 >128 - 64 >128 >128 >128 >128 >128 >128 >128 >128 >128 Bacillus (Bacillaceae Gram+) Bacillus subtilis CIP 5262 >128 128 - 64 >128 >128 >128 >128 >128 >128 >128 128 128 Enterobacteriaceae (Gram-) E. coli ATCC 25922 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Klebsiella pneumoniae API ATCC 35657 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 64 >128 >128 Enterobacter cloacae API Ec10 ATCC13047 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Serratia marcescens CIP 103551 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Pseudomonadaceae (Gram-) Pseudomonas aeruginosa CIP 5933 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 (>32) >128 >128 Acinetobacter (Moraxellaceae Gram-) Acinetobacter baumanii ATCC 19606 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 (>32) >128 >128 Haemophilus (Pasteurellaceae Gram-) Haemophilus influenzae ATCC 49766 >128 32 - 32 >128 >128 >128 >128 >128 >128 >128 >128 - The MBC was determined using a macro-method. Sterile tubes were filled with a primary bacterial inoculum prepared in Mueller Hinton broth as above (106 CFU/mL of final inoculum) and indolic compounds were added at twofold serial concentrations (0.25-64 mg/L of final concentrations). After 18 hours incubation of cultures, ten-fold serial dilutions of the cultures with no visible bacterial growth were prepared, and 100µl of each dilution were inoculated to Mueller Hinton agar media for 24-48 hours. CFU counts were then determined and the MBC corresponded to the minimal indolic compound concentration for which 99.9% of more bacterial cells were killed after 18 hours of incubation.
- The method described by Motyl et al. [M. Motyl, K. Dorso, J. Barrett, R. Giacobbe, Basic Microbiological Techniques Used in Antibacterial Drug Discovery. Current Protocols in Pharmacology. UNIT 13A.3. January, 2006 ] was used.
- Killing curves corresponded to the measure of the kinetic of bactericidal activity of indolic compounds over time (time-kill curves) or after 18h incubation of cultures according to different drug concentrations (concentration-killing curves). Sterile tubes were inoculated with : 1/ sterile Mueller Hinton broth, to serve as negative control ; 2/ a drug-free bacterial inoculum, to serve as a growth control; 3/ a bacterial inoculum (105 CFU/ml of final concentration) with various concentrations of the tested indolic compound. The tubes were incubated at 37 °C with agitation (50 rpm). Bacterial inocula are determined in each tube using the CFU count method at the beginning of the experiments, and then after 18h for concentration-killing curves, or after 1h, 2h, 4h, 8h and 18h for time-kill curves. A significant bactericidal effect corresponds to reduction of the initial bacterial load of 3 logs or more at any time of incubation.
- The mutation frequency is the number of individuals in a population with a particular mutation. In the present case, the mutation frequency was determined for a specific bacterial species and a specific indolic compound. Mueller Hinton agar plates containing various indolic compound concentrations, i.e., MIC x 2, MIC x 4, MIC x 8, and MIC x 16 were prepared. These plates were inoculated with various bacterial suspensions: 107, 108 or 109 UFC/ml. After 24 hours incubation of media at 37 °C, CFU were numerated. The mutation frequency corresponded to the ratio of resistant mutants counted on a specific plate to the CFU count of the primary inoculum, expressed as a percentage.
- The mutation frequency was determined for S. aureus ATCC 25923 strain.
- In vitro mutant strains that resisted to the most active indolic compounds were selected. A bacterial inoculum (5 x 104 CFU/mL) was prepared in Mueller Hinton broth and dispensed in a 24-well microtiter plate (1 ml per well). Each row received two-fold serial concentrations of the tested indolic compound (1/2 to 16 times the MIC of the wild-type strain). Plates were incubated 72-96 hours, and bacterial growth obtained in the well with the highest indolic compound concentration were harvested, diluted 1/40 and dispensed in a new 24-well microtiter plate with increased drug concentrations (1/2 to 16 times the new MIC). The procedure was repeated several fold until we obtained high-level resistant mutants. The final and intermediate resistant mutant populations were all kept frozen at -80 °C for later analysis.
- Several independent mutant strains with acquired resistance to indolic compounds in S. aureus and in S. epidermidis strains have been selected. Selection of resistance was slow and difficult to obtain, but high-level resistant mutants (MIC of 64-128 mg/L) could be isolated. These mutants have been used to better characterize the mode of action of indolic compounds and resistance mechanisms that may be developed by Staphylococcus species to resist the action of these new antibiotics.
- The efflux pump inhibition potential of the bis-indolic derivatives was tested using two steps. In a first step, the intrinsic antibacterial activity of the compounds was assayed against the following strains:
- Staphylococcus aureus (ATCC 25923), Staphylococcus aureus 1199B, which is resistant to fluoroquinolones due notably to the overexpression of the NorA efflux pump (G. W. Kaatz, S. M. Seo, Antimicrob. Agents Chemother. 1995, 39, 2650-2655) and Staphylococcus aureus K2378 which overexpresses the efflux pump NorA from a multicopy plasmid (S. Sabatini, G. W. Kaatz, G. M. Rossolni, D. Brandini, A. Fravolini J. Med. Chem. 2008, 51, 4321-43330.
- The following experimental protocol was used: indolic derivatives (initially solubilised in DMSO at 10 mg/mL) were dispensed in a 96-wells microplate by two fold serial dilutions in Muller-Hinton medium (MH, Bio Rad) using a Biomek 2000 (Beckman) handling robot. 100 µL of the bacterial inoculum (an overnight culture at 37 °C in 5 mL MH diluted 100-fold) was then added in each well. The total volume was 200 µL in each well and the final bacteria concentration 106 CFU/mL (CFU: colony forming unit). The highest final indolic derivative concentration was 128 mg/L. Growth was assayed with a microplate reader by monitoring absorption at 620 nm after 1, 2, 5, 7 and 24 h incubation at 37 °C. In addition, the plates were read visually after 24 hours incubation. Cultures containing 5 µL DMSO were used as growth controls. In addition, two controls containing a sub-inhibitory or a inhibitory antibiotic concentration for the tested strain were performed. The antibiotics used were ampicillin (0.5 and 32 µg/mL) for E. coli, kanamycin (0.5 and 16 µg/mL) for S. aureus ATCC 25923, ciprofloxacin (4 and 64 mg/L) for S. aureus 1199B, ciprofloxacin (0.5 and 2 mg/L) for S. aureus K2378. All experiments were performed in duplicate.
- In spite of slight differences in the experimental protocol, all compounds described in the present invention showed similar antibacterial activity (at most a 4-fold difference was observed between MIC values) using the experimental procedure described in paragraph 9.1 and in the present paragraph).
- Efflux pump inhibition assays were then performed against resistant Staphylococcus aureus strains SA 1199B and SA K2378 for bis-indolic derivatives. A serial dilution method was used to test the bis-indolic compounds (maximal concentration 128 mg/L) in the presence of a sub-inhibitory concentration of the ciprofloxacin (4 mg/L, MIC/4 and 2 mg/L, MIC/8) or less for SA 1199B and ciprofloxacin (0.5 mg/L, MIC/4 and 0.25 mg/L, MIC/8) for SA K2378. The minimal inhibitory concentration (MIC) of the bis-indolic compound allowing a complete inhibition of the bacterial growth in the presence of ciprofloxacin was determined.
- Results are presented in table II:
TABLE II Compounds CMI, mg/L (Ciprofloxacin concentration, mg/L) Staphylococcus aureus 1199B Staphylococcus aureus K2378 2 0.5 (4) - 2 (2) 6a <0.125 (4) 8 (0.25) 6b 0.5 (4) 16 (0.25) 6c 0.25 (4) 16 (0.25) 6d < 0.125 (4) 8 (0.25) 6f <0.25 (4) 1 (0.25) 1 (0.5) - In vitro cytotoxicity was assayed on three cell lines - KB (human mouth carcinoma), MCR5 (human lung fibroblast) and HCT 116 (human colon tumor). Results are presented in table III as % of cellular growth inhibition in presence of 10-5 M and 10-6 M of the tested bis-indolic derivatives.
- IC50 are presented in table IV.
TABLE III Compounds KB MRC5 HCT116 10-5 M (10-6 M) 10-5 M (10-6 M) 10-5 M (10-6 M) 2 97±1 (33±8) 100±2 (10±5) 96±1 (53±4) 3 100±1 (4±3) 98±1 (0±3) 97±1 (0±13) 4 76±5 (0±7) 51±9 (0±3) 58±4 (0±9) 5 91±3(0±11) 85±2 (6±3) 80±3 (10±6) 6a 20±13 (0±18) 28±9 (0±15) 37±6 (0±5) 6b 9±4 (0±8) 15±11 (0±3) 21±10 (2±13) 6c 66±8 (0±8) 6±16 (0±17) 53±3 (8±2) 6d 53±5 (0±19) 0±3 (0±26) 41±4 (4±13) 6e 29±6 (0±2) 0±10 (0±12) 24±6 (3±8) 6f 92±3 (0±13) 39±4 (0±12) 81±2 (0±4) 7 4±11 (0±3) 0±12 (0±14) 22±7 (0±8) -
Compound HCT116 Compound HCT116 IC50 IC50 4 4.55/6.07 5 10.1 / 10.3
Claims (18)
- Compounds of the following formula I:X and X' represent independently from each other O or S, anda) R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4 and R'5 represent independently from each other:- H,- a linear or branched (C1-C7)alkyl, if appropriate substituted by:a halogen, a hydroxyl group, a ORa or NRaRb, wherein Ra and Rb represent: H, a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group- a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group,- F, Cl, Br, I, CF3, OH, ORa, OCF3, COCF3, NH2, NHRa, NRaRb, wherein Ra and Rb represent:H, a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, an aryl substituted or not, CH2-aryl, CO-(C1-C7)-alkyl, CO-aryl, CO2-(C1-C7)-alkyl, CO2-aryl, wherein aryl is a substituted or not aromatic group or a substituted or not heteroaromatic group,- CN and NO2 provided that R1, R2, R3, R4, R5, R'1 are different from CN and NO2.- (CH2)n-Z, -(CH2)n-OH, -(CH2)n-CO2-(C1-C7)-alkyl, -(CH2)n-CO2 wherein n = 2 to 12, Z is an halogen, and alkyl being as defined above.R represents H, a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CH2NHCO2-(C3-C7)-cycloalkyl, CO2H, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(C1-C7)-alkyl, CONH-(C3-C7)-cycloalkyl, CONH-aryl, CONH-(CH2)nOH, CONH-(CH2)nNRaRb, wherein n = 2 to 12 and Ra, Rb, aryl and alkyl being as defined above.R6 and R'6 represent independently from each other H, (C1-C7)-alkyl, SO2aryl, whereinaryl being as defined above, OH, O-(C1-C7)-alkyl, CO-(C1-C7)-alkyl, CO-aryl, CH2NH2, CH2NHRa, CH2NaRb, Si(Rc)3, the Rc groups being identical or different andrepresenting independently of each other a linear or branched (C1-C7)-alkyl, a (C3-C7)-cycloalkyl, or an aryl, aryl and alkyl being as defined above,R7 represents H, OH, ORa, Ra being as defined above,orb) R and R7 are joined together to form a cycle of formula I-a:- N-R8 wherein R8 represents H, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, CO-(C1-C7)-alkyl, CO-(C3-C7)-cycloalkyl, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl,- O,- S,- CH2, CHR8 wherein R8 represents (C1-C7)-alkyl, (C3-C7)-cycloalkyl, CO-(C1-C7)-alkyl, CO-(C3-C7)-cycloalkyl, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl,- m = 0, 1said cycle being optionally substituted by OH, a linear or branched O(C1-C7)-alkyl, a O(C3-C7)-cycloalkyl, NH2, or NRaRb, Ra and Rb being as defined above, R1, R2, R3, R4, R5, R'1, R'2, R'3, R'4, R'5, R6 and R'6 being as defined above,
orR1, R2, R3, R4, R5, R'1, R'2, R'3, R'4, R'5, R6 and R'6 being as defined above,and their pharmaceutically acceptable salts,
for use as a medicament, suitable especially for an antibacterial activity and/or NorA efflux pump inhibitor. - Compounds according to claim 1, wherein:X and X' are as defined above,R1, R2, R3, R4, R5, R6, R'1, R'2, R'3, R'4, R'5 and R'6 are as defined above,R represents H, a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CH2NHCO2-(C3-C7)-cycloalkyl, CO2H, CO2-(C1-C7)-alkyl, CO2-(C3-C7)-cycloalkyl, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(C1-C7)-alkyl, CONH-(C3-C7)-cycloalkyl, CONH-aryl, CONH-(CH2)nOH, CONH-(CH2)nNRaRb, wherein n = 2 to 12 and Ra, Rb, aryl and alkyl being as defined above.R7 represents H, OH, ORa, Ra being as defined above,
- Compounds according to claim 1, wherein:X and X' are as defined above,R1, R2, R3, R4, R5, R6 R'1, R'2, R'3, R'4, R'5 and R'6 are as defined above, andR and R7 are joined together to form a cycle of formulas (I-a) and (I-b) as defined above
- Compounds according to claim 1 to 3, wherein the antibacterial activity is against Gram-positive and Gram-negative bacteria.
- Compounds according to claim 1 to 4, wherein said bacteria are resistant to conventional antibiotics.
- Compounds according to anyone of claims 1 to 5, wherein the antibacterial activity is against Staphylococcus species, in particular Staphylococcus aureus, especially Staphylococcus aureus resistant to β-lactams (including methicillin-resistant strains, also referred as MRSA), Staphylococcus aureus resistant to glycopeptides (vancomycin-resistant or glycopeptides-resistant strains, also referred as VISA or GISA) and Staphylococcus aureus resistant to fluoroquinolones.
- Compounds according to anyone of claims 1 to 6, having further an antifungal and/or antiviral activity.
- Compounds according to anyone of claims 1, 2 and 4 to 10, of the following formula
VR3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I,R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb. - Compounds according to claim 11, of formula V wherein:R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I, at least one of R3, R4, R'3 and R'4 represents F, Cl, Br, I,R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb.
- Compounds according to claim 11, of the following general formula VI:R3 and R'3 represent independently from each other H, F, Cl, Br, I, at least one of R3 andR'3, represents F, Cl, Br, I,R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb,
in particular compounds of formula VI selected from the group consisting of :R4 and R'4 represent independently from each other H, F, Cl, Br, I, at least one of R4 andR'4 represents F, Cl, Br, I,R represents a (C1-C7)-alkyl, CH2NHCO2(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb,
in particular compounds having the following structure:R represents a (C1-C7)-alkyl, CH2NHCO2-(C1-C7)-alkyl, CO2H, CO2-(C1-C7)-alkyl, CONH-(CH2)nOH, (CH2)nOH, CH2NH(CH2)n-OH, CH2NH(CH2)n-NRaRb, CONH-(CH2)nNRaRb, in particular compounds having the following structure:Y = N-R8 = NBoc ou NH, ouY = CH2, CH-R8, R8 being as defined in claim 1,R3, R4, R'3 and R'4 represent independently from each other H, F, Cl, Br, I.m = 0 or 1, - Pharmaceutical composition comprising a compound of formula I, in association with a pharmaceutically acceptable vehicle.
- Pharmaceutical composition according to claim 21, administrable by oral route at a dose comprised from about 10 mg/kg to about 200 mg/kg.
- Pharmaceutical composition according to claim 21, administrable by intraveinous route at a dose comprised from about 5 µg/kg to about 50 mg/kg.
- Pharmaceutical composition according to anyone of claims 21 to 23, comprising a compound defined in claim 11, or a compound defined in claim 13; or a compound defined in claim 15, or a compound defined in claim 17 or a compound defined in claim 19.
- Pharmaceutical composition according to claim 21 to 24, comprising further:- at least one antibiotic compound, in particular from the fluoroquinolones family, such as ciprofloxacin, norfloxacin, pefloxacin, enofloxacin, ofloxacin, levofloxacin or moxifloxacin,
said pharmaceutical composition being used for simultaneous or separate use or use spread over time intended for the treatment of pathologies associated with bacterial infections for which a resistance to the antibiotic, in particular from the fluoroquinolones family exists.
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ES11305964.6T ES2461997T3 (en) | 2011-07-22 | 2011-07-22 | New bis-indole derivatives, their uses, in particular as antibacterials |
PCT/EP2012/064339 WO2013014104A1 (en) | 2011-07-22 | 2012-07-20 | Bis-indolic derivatives, their uses in particular as antibacterials |
CA2842508A CA2842508C (en) | 2011-07-22 | 2012-07-20 | Bis-indolic derivatives, their uses in particular as antibacterials |
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